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Chapter 50
Diabetes Mellitus
B e t s y A. C a r l i s l e
L i s a A. K r o on
M a r y An n e K o d a - Ki m ble
P . 5 0 -2
A wo r l d wi d e ep i de mi c o f d i ab e te s m el li t us is l o omi n g . Th e C en t e rs fo r D ise a se C on t r ol an d
P r e ve n ti o n ( C D C ) p re d ict s th e n a ti o na l i nc id e nc e o f di ab e te s wi ll r is e b y 3 7 . 5% b y th e yea r
2 0 2 5 a nd b y 1 7 0% in deve l o pi n g c ou n tr i es o ve r th e ne xt 3 0 ye a rs . O f p a rti c ul a r c on ce r n i s t he
a l a rm in g i nc r e as e i n t he p r e va le nc e o f t ype 2 d iab e t es i n b o th ad u lt s a n d c h il d re n . I n 2 0 02 , a n
e s ti ma t ed 18 . 2 m il li o n pe o pl e , o r 6. 3 % o f t he U nit e d St a te s p o pu la t io n , ha d di ab e t es . O f t he se ,
5 . 2 m il li o n o r a b ou t o n e -t h i rd we r e u nd ia g no se d . 1 B u t t he r e i s g oo d n e ws . C l in ic a l s tu di es
h a ve af f i rm ed th a t t yp e 2 d i ab e te s ca n b e de la yed o r p r e ve nt e d in hi g h - ris k p op u la t io ns an d
t h a t g oo d g l yce mi c c on t ro l an d o t he r in t er ve n ti o ns ca n s lo w t h e d e va st a tin g c om p li ca t io ns of
d i ab e te s . N e ve r th e le ss , b r o a d im pl em e nt a ti o n o f g u id e li n es a n d g oa ls es ta b li sh e d b y t he
A m e ri c an D ia be t es As soc i at i on an d o t he r s h as be e n s lo w. 2 , 3
P . 5 0 -3
Definition, Classification, and Epidemiology
D i a b et es is a s ynd r om e th a t i s c au se d b y a re l at ive o r an ab so l ut e l ac k o f i ns u li n . C l in ic al l y, it
i s c ha r ac t e ri ze d b y s ympt o ma t ic gl uc os e i n to le r an c e as we l l as a l te r a ti ons in li p id an d p r ot e in
m e ta b ol is m. O ve r t he l on g te r m, t he se m e ta b ol ic a b no r ma li t ie s , p ar t ic ul a rl y h yp e r gl yc em ia ,
c o nt r i bu t e t o t he d e vel opm e nt o f co mp l ic at i on s suc h a s re ti n op a th y, n ep h ro p a th y, an d
n e u ro p at h y.
C l i ni c al l y, e t io lo g ic al l y, a n d g e ne t ic al l y, d i ab e tes is a h et e ro g en e ou s g r ou p of di so r d er s .
N e ve r t h el es s, mo st ca ses o f d ia be t es m e ll i tu s can b e as si g ne d t o t ype 1 o r t yp e 2 d i ab e te s
( d e sc ri b ed be l o w) . Th e te r m g es t a ti on a l d ia be t es m el l it us ( G D M) i s us ed to d esc r i be gl uc os e
i n t ol e ra nc e th a t h as i t s on s et du r i ng pr e gn a nc y, an d gl uc os e i n to l er a nc e th a t c an n ot be
a sc r i be d t o c au se s c on sis t en t wi t h th es e t h re e c la ss i fi ca t io ns a re ad d r esse d m o r e sp ec i fi ca l l y
( e . g . sp e ci fi c g e ne ti c d e fe c ts in in su li n a c ti on ; dru g - in d uc ed di a be t es ; p an c r ea t ic d is e as e ).
S u b cl in ic a l g lu co se in t ole r a nc e o r “p r e di ab e te s ” is id e nt i fi e d as im pa i re d g l uc os e t o le r an c e
( I G T) o r i mp ai r e d f as ti n g g l uc os e ( I F G ) .
A p p r o xi m a te l y 5% to 10% o f t h e di a gn os e d d ia be t ic po p ul a ti on h as t yp e 1 d ia be t es , wh i ch
r e s ul ts f ro m a u to im mu ne d es t r uc ti o n o f t h e p an c re a t ic β -c el ls . A t cl i ni ca l p r e se n ta t io n , t he se
p a t ie n ts h a ve l i t tl e o r n o p a nc r ea t ic re se r ve , h a ve a te nd e nc y t o d e vel o p k e to ac i do si s , a nd
r e q ui r e e xo g e n ou s i ns u lin t o s us ta i n l if e . Th e in cid e nc e o f t ype 1 d ia b et es p e aks d ur i ng
p u b er t y b et we e n 10 an d 1 4 ye a rs o f ag e , a l t h ou gh t he ag e a t on se t ra n ges f ro m 9 m o nt hs t o 2 8
ye a r s . A p p ro xi m a t el y 7 .4% o f a du l ts wh o a re di agn o se d wi t h d ia b et es be twe e n 3 0 a n d 7 4 ye a rs
o f ag e h a ve t ype 1 d ia b et e s . I n t he s e i nd i vid u al s, t h e r a te o f p an c re a ti c de s t ru c ti on se em s t o
o cc u r m o re s l o wl y, l ea din g to a l a te r o ns e t a n d le ss ac u te p re se n ta t io n 4 , 5 ( Ta b le 5 0 - 1 ) .
Table 50-1 Type 1 and Type 2 Diabetes
Characteristics
Type 1
Type 2
Other names
Previously, type I; insulindependent diabetes mellitus
(IDDM); juvenile-onset diabetes
mellitus
Previously, type II; non–insulindependent diabetes mellitus
(NIDDM); adult onset diabetes
mellitus
Percentage of
diabetic
population
5–10%
90%
Age at onset
Usually <30 yr; peaks at 12–14
yr; rare before 6 mo; some
adults develop type 1 during the
fifth decade
Usually >40 yr, but increasing
prevalence among obese children
Pancreatic
function
Usually none, although some
residual C-peptide can
sometimes be detected at
diagnosis, especially in adults
Insulin present in low, “normal,”
or high amounts
Pathogenesis
Associated with certain HLA
types; presence of islet cell
antibodies suggests autoimmune
process
Defect in insulin secretion; tissue
resistance to insulin; ↑ hepatic
glucose output
Family history
Generally not strong
Strong
Obesity
Uncommon unless
“overinsulinized” with
exogenous insulin
Common (60–90%)
History of
ketoacidosis
Often present
Rare, except in circumstances of
unusual stress (e.g., infection)
Clinical
Moderate to severe symptoms
Mild polyuria, fatigue; often
presentation
that generally progress relatively
rapidly (days to weeks):
polyuria, polydipsia, fatigue,
weight loss, ketoacidosis
diagnosed on routine physical or
dental examination
Treatment
Insulin
Diet
Diet
Exercise
Exercise
Oral antidiabetic agents (αglucosidase inhibitors,
biguanides, non-sulfonylurea
insulin secretagogues,
sulfonylureas,
thiazolidinediones)
Insulin
HLA, human leukocyte antigen.
Mo s t p e op l e wi t h di a be t es ha ve t yp e 2 d i ab e te s, a h et e r og en e ou s d is o rd er t h at is
c h a ra ct e ri ze d b y o b es it y, β - c el l d ys fu nc t io n , r es is t an ce t o i ns ul in ac t io n , a n d i nc r ea se d he pa t ic
g l uc os e p r od u ct i on . Bo t h t h e i nc id e nc e a nd p re val e nc e o f d i ab e te s i nc r eas e d r am a ti ca l l y wi t h
a g e . F o r e xa m p le , th e p re va l e nc e o f s el f - re p or t ed d i ab e te s is 1 .1 % a mo ng p e rs o ns 2 0 to 39
ye a r s o f ag e a nd 12 . 6% a m on g p e rs o ns 6 5 t o 7 4 ye a r s o f ag e . 6 Th e p r e va l en c e o f t yp e 2
d i ab e te s d i ff e rs am on g et h n ic p o pu l at io n s. R el a tive t o c a uc as ia ns , th e p re va l e nc e o f
d i ag n os ed an d u n di a gn os e d t yp e 2 di ab e t es i s h ig h e r i n A f r ic an Am e r ic ans ( 1. 6 ti me s ),
Me xi c a n A me r ic a ns (1 . 9 t i me s ), an d N at i ve Am e ric a ns . 7 G r o wt h in t he ag in g po p ul a ti on as we l l
a s g r e at e r ra ci al an d e t hn i c d i ve rs it y a r e ca us i ng p r e di ct e d i nc re a se s i n th e p re va le nc e of
d i ag n os ed di a be t es fr o m 4 . 2% t o 5 .2 % o f th e p opu l a ti on b y 20 2 0. 8
D i a b et es is a se r io us con d i ti on t ha t p l ac es p e op le a t r is k f o r g r ea t e r mo rb i di t y a nd m o r ta li t y
r e l at i ve to th e n o nd i ab e tic po p ul a ti o n. Fo r e xa m ple , co mp a re d wi t h t h e g en e r al po p ul a t i on , th e
m o r ta li t y r a te fo r pe o pl e wi t h t yp e 1 d ia be t es is 5 t o 12 ti me s h ig h er , an d f o r ad u lt s wi t h t yp e 2
d i ab e te s , i t i s t wo t im es h i gh e r . Mo r b id i t y a ls o i s g r e a te r fo r p e op l e wi t h di a be t es an d i s
p r i ma r il y r el a te d to ac ute a nd c h r on ic c om p li ca t io n s as s oc ia t ed wi t h th e c o nd i ti on . 9
Me d i c a l m an a ge me n t o f p e r so ns wi t h a di a gn os is o f di ab e te s i s co s tl y. In 2 0 0 2, th e a n nu a l p er
c a pi t a h ea l th c a r e e xp e nd i t ur e s f o r p eo pl e wi t h d ia b e te s we r e a pp r o xi m a te l y 2 .4 ti m es h i gh e r
t h a n t ho se f o r in d i vid u als wi t h ou t di ab e te s . I n o ne s tu d y 8 , 1 9% of t ot a l he a l th c a r e co s ts i n t h e
U n i t ed S ta t es wa s i nc u r re d b y p e op l e wi t h di a be te s , e ve n t h ou g h t he y
P . 5 0 -4
r e p r es en t on l y 4% of th e p o pu la t io n . Ho sp i ta l c ost s , n u rs in g h o me c a re , ph ys ic i an vis i ts , a n d
m e di ci n es m ad e u p th e m a jo r it y o f th es e e xp e n di t u re s . B ec a us e m an y e xp e n di tu r es a re r el a te d
t o t re a tm en t of lo n g - t e rm c om pl ic a ti o ns , c on si d era b le e ff o r t h as b e en di r ec t ed t o wa r d e a rl y
d i ag n os is an d m et a bo li c c o nt r o l o f p at i en ts wi t h di a be t es .
Carbohydrate Metabolism
A n u nd e rs t an di n g o f t h e s i gn s a nd s ym p to ms asso c ia t ed wi t h d i ab e te s i s b a se d o n a
k n o wl e dg e o f g l uc os e me t a bo li sm an d t h e me t abo l ic ef f ec ts of in s ul in in d i ab e ti c a n d
n o n di ab e ti c s ub je c ts d u rin g th e fe d ( p os t pr a nd i al ) a n d f as t in g ( p os t ab so r pti ve ) st a te s . 1 0
H o m eo s ta t ic m ec ha n isms ma in t ai n p l asm a g l uc os e c on c en t ra t io ns be t we e n 55 an d 1 4 0 mg / dL
( 3 . 1 t o 7 . 8 mm o l/ L ) . A m in i mu m co nc e n tr a ti o n o f 4 0 to 60 mg / dL ( 2. 2 t o 3 .3 mm ol / L ) is r eq u ir e d
t o p ro vi d e a de qu a te f ue l f o r th e c en t r al ne r vo us s ys t em ( C N S ), wh i c h use s g l uc os e a s i ts
p r i ma r y en e r g y s ou r ce an d is i n de p en de n t o f i nsu l in f or gl uc o se ut il i za ti on . W he n b lo o d
g l uc os e c on ce n t ra t io ns exc e e d t h e r ea bs o r pt i ve ca p ac i t y o f th e k id n e ys ( ap p r o xi m a te l y 18 0
m g /d L ) , g lu co se sp il ls int o t he ur i ne r es ul t in g i n a l oss o f ca l or i es an d wat e r . Mu s cl e a n d f at
a l so us e g lu co se as a ma j o r s ou rc e of en e rg y, bu t t he se ti ss ue s r e qu i re in s ul in f o r gl u co se
u p t ak e. I f g lu co se is un ava i l ab l e, t he se ti ss ue s ar e a bl e t o u se ot h e r su bst r a t es s uc h a s a mi no
a c id s a nd fa t t y ac id s f o r f u e l.
Postprandial Glucose Metabolism in the Nondiabetic Individual
A f t e r f o od is i n ge s te d , b lo o d g lu c os e co nc e nt r a tio n s r is e a n d s ti mu la t e i ns u li n r e le as e . I ns u li n
i s th e k e y to ef f ic ie n t g luc os e u t il i za ti o n. I t p r om ot e s t h e u pt ak e o f gl uc ose , f at t y ac id s , a nd
a m in o a ci ds as we l l a s th e i r c on ve r si on t o st o r age f o rms in mo st t iss u es . I n mu sc le , i ns u li n
p r o mo t es th e u p ta ke of gl u co se an d i ts st o r ag e as gl yc og e n . I t a ls o s ti mu la t es t he up t ak e o f
a m in o a ci ds an d t h ei r c on ve r s io n t o p r o te in . In ad i po s e t iss u e, gl uc o se is c on ve r t ed t o f r ee
f a t t y ac id s a nd st o re d as t r i gl yc e ri de s . I ns ul i n a lso p r e ven ts a b r ea kd o wn o f t he se t ri gl yc e ri d es
t o f re e fa t t y ac id s, a f o rm t ha t m a y be t ra ns p or te d to o th e r t is su es fo r u ti l i za ti on . Th e l i ve r
d o es no t re q ui r e i ns ul i n fo r gl u co se t ra ns p or t , b u t i ns u li n f ac i li t at es th e c on ve r s io n o f g l uc os e
t o gl yc og e n a nd f re e fa t ty a c id s . Th e la t te r a re es t e ri f ie d t o tr i gl yc e ri de s , wh i c h a r e
t r a ns p or t e d b y ve r y - l o w- d e ns i t y l i po p ro t ei ns ( V LD L ) t o a di p os e a nd m u scl e ti ss ue .
Fasting Glucose Metabolism in the Nondiabetic Individual
A s bl o od gl uc os e c on ce nt r a t io ns d ro p t o wa r d no rm a l d u ri ng t he fa st i ng s ta t e , i ns ul i n r el e as e i s
i n hi b it e d. S im ul t an e ou sly, a n um be r of c o un t e r -re g ul a to r y h o rm o n es t ha t o p p os e t he ef f ec t o f
i n su li n a n d p r om ot e a n in c r ea se in bl oo d s u ga r ar e r el e as ed ( e. g . , gl u ca go n , e p in e ph r in e ,
g r o wt h h o rm on e , g lu co co r t ic oi d s) . As a r es u lt , se ve r a l p r oc es se s ma i nt a in a m in im um bl o od
g l uc os e c on ce n t ra t io n f or t h e C N S . G l yco g en in th e li ve r i s b r ok en do wn i n t o g l uc os e
( g l yc og en o l ysi s) ; am in o a c id s a r e t r an sp o r te d f r om mu sc le to li ve r , wh e r e t h e y ar e c o n ver t e d
t o gl uc os e th r ou g h g lu con e o ge ne si s ; u pt ak e o f glu c os e b y i ns ul in - d ep en de n t ti ss ue s is
d i mi ni sh e d t o c on se r ve gl u co se fo r th e br a in ; a n d f i na l l y, t r ig l yce r id e s a re b r ok e n d o wn in t o
f r e e f a t t y a ci ds , wh i ch a re us e d a s al t e rn a ti ve f uel so u rc es .
Type 1 Diabetes
Pathogenesis11
Th e l os s o f i ns u li n s ec r et i o n i n t yp e 1 di ab e te s me l li t us re s ul ts f ro m a ut o im mu n e d es t ru c ti on o f
t h e i ns u li n -p r o du ci ng β - ce l ls in th e p a nc r ea s, wh ic h i s t h ou gh t to be t ri g ge r e d b y
e n vi r on me n ta l fa ct o rs , su c h as vi r us es o r t o xi n s, i n g e ne t ic al l y s us ce p ti b le i nd i vid u al s. Th i s
f o r m o f d ia b et es is ass oc i at e d cl os e l y wi t h h is t oc om p at i bi li t y a nt i ge ns ( HL A - D R 3 o r H L A - D R4 )
a n d t h e p r es en ce of ci r cu l a ti ng in su l in an d i sl e t c e ll an t ib od i es ( I C As ) . Th e c a pa ci t y o f n o rm al
p a nc r ea t ic β -c e ll s t o s ecr e t e i ns u li n f a r e xc e e ds th e no r ma l a mo un t s n ee de d to co n tr o l
c a r bo h yd ra t e , f at , an d p ro t e in m e ta b ol is m. A s a re s ul t , t h e cl i ni ca l o ns e t o f t yp e 1 d i ab e te s is
p r e ce de d b y a n e xt e n s i ve as ym p to ma t ic p e r io d du r i ng wh i ch β - ce ll s a r e de s t ro ye d ( F i g. 50 - 1 ) .
β - C e l l d es t r uc ti o n ma y oc cu r r ap id l y b ut is m o re li k el y t o t ak e p l ac e o ve r a p e ri od o f we e ks ,
m o nt hs , o r e ve n ye a rs . Th e ea r li es t de t ec ta b le abn o r ma li t y in in s ul in s e cre t i on is a p ro g re ss i ve
r e d uc t io n o f i mm ed i at e or f i rs t - ph as e p la sm a i n s ul i n r es p on se . H o we ve r , th i s i ni t ia l im p ai r me n t
h a s f e w d e t ri me n ta l e f fec t s o n o ve r al l g lu co se hom e os ta si s , a nd pl as ma gl u co se
c o nc en t r at i on s r em a in no r m al . Mo s t a f fe c te d i nd ivi d u al s h a ve c i rc ul a ti ng a n t ib od i es to is le t
c e ll s o r t o th ei r o wn in sul i n a t t h is s t ag e o f th e d is e as e. Th e se r ep r es en t m a rk e rs of an
o n g oi ng au t oi mm un e p r oc es s t h at cu lm in a te s i n typ e 1 d i ab e te s. F as ti n g h yp e r gl yc em i a oc cu r s
wh e n β - c el l m as s is r ed uc e d b y 8 0% to 90 % . I ni t ia l l y, o n l y p os t p ra n di al hyp e r g l yce mi a o cc u rs ,
b u t a s i ns ul i n se c re t io n b e co me s f u r th e r c om pr om is e d, p ro g re ss i ve f a st in g h ype r gl yc em i a is
s e en .
O n p r es en t a ti on , ap p ro xi m a te l y 65 % to 85 % o f p at i e nt s h a ve c ir c ul a ti ng an t i bo di es di r ec t ed
a g ai n st is le t c el ls an d 2 0% t o 6 0% o f p at i en ts ha ve me as u r ab le an t ib o di es d i re c te d
P . 5 0 -5
a g ai n st in su li n . W ith in 8 t o 10 ye a rs fo ll o wi n g c li ni c al pr e se n ta t io n , β - ce ll lo ss is c om p le t e a nd
i n su li n d e fi ci e nc y is ab so l u te . Ci r cu l at i ng I C As ca n no lo n ge r b e d e te c te d.
View Figure
FIGURE 50-1 Pathogenesis of type 1 diabetes. In an
individual with a genetic predisposition, an event (such as a
virus or toxin) triggers autoimmune destruction of the
pancreatic β-cells, probably over a period of several years.
When the number of β-cells diminishes to approximately
250,000, the pancreas is unable to secrete sufficient insulin
and intolerance to glucose ensues. At this point, a stressful
event, such as a viral infection, can produce acute symptoms
of hyperglycemia and ketoacidosis. Once the acute event has
passed, the pancreas temporarily recovers, leading to a
remission (honeymoon period). Continued destruction of the
β-cell ultimately leads to an insulin-dependent state.
Clinical Presentation
A l t h ou gh t he on se t o f t yp e 1 d ia b et es ap p ea r s t o b e a b r up t , e vi de nc e n ow e xi s t s fo r a n
e xt e n d e d p r ec li n ic al pe r io d th a t c an p re ce de ob vio u s s ymp t om s b y s e ve r al ye a rs . As in su li n
s ec r e ti o n b ec om es c om pr o m is ed , p r og r es si ve f ast i n g h yp e rg l yce mi a o cc u rs . W he n p la sm a
g l uc os e c on ce n t ra t io ns exc e e d t h e n or ma l re n al th r e sh ol d o f ap p ro xi m a t ely 1 8 0 m g /d L (1 0
m mo l /L ) , g l uc os u ri a re sul t s i n a n o sm ot ic di u re si s, p r od uc i ng th e c la ss ic sym p t om s o f p ol yu r i a
wi t h c om p en sa t or y p o l ydi p si a . I f s ymp t om s a r e un t r e at e d, we i g ht lo ss occu r s a s g lu co se
c a lo r ie s a r e l os t i n t h e ur i n e a nd bo d y f at an d p ro t e in s t o re s a r e b r ok en d o wn o wi n g to
i n c re as ed r a te s o f l ip ol ys is an d p r o te o l ys is . Mu sc l e b eg in s t o m e ta bo l i ze i t s o wn g l yco g en
s t o re s a nd f at t y ac id s f o r f u el , a n d t h e li ve r be g ins t o me t ab o li ze f re e f a t t y a ci ds t ha t a r e
r e l ea se d i n re sp o ns e t o e p in e ph r in e a n d l o w i ns ul i n c on ce n t ra t io ns . An abs o lu t e l ack o f i ns ul in
m a y ca us e e xc e s si ve m ob i li za t io n o f f re e f a tt y a ci d s t o t h e li ve r , wh e r e t he y a r e m e ta bo l i zed to
k e to n es . Th is c an r es ul t i n k e to n em ia , k e to nu r i a, a n d , u lt im a te l y, k e to ac i do s is . Pa ti e nt s
p r e se n t wi t h co mp la i nt s o f f at ig u e , si g ni fi c an t wei g h t l oss , po l yu ri a , a nd po l yd ip si a . A
s i gn i fi ca n t e le va t io n i n gl yc os yl a te d he mo gl o bi n c o nf i rm s we e k s o r m on t hs o f p re c ed in g
h yp e r gl yc em i a.
B e c au se gl uc os e p r o vi des an e xc e ll e nt me di u m f or m ic r oo r ga n ism s , p at i ent s m a y p re se n t a ls o
wi t h r e cu r r en t re s pi r at o ry, va g i na l , a nd o th e r i nf ec t io ns . P at ie n ts al so m ay e xp e r i e n ce bl u r re d
vi s i on s ec o nd a r y to os mo t ic a ll y i nd uc e d ch a ng es i n t h e l en s o f t h e e y e . Tr e a tm e nt wi t h i n su li n
i s e ss en t ia l to pr e ve n t se ve r e de h yd ra t io n , k et o ac i do si s, an d d e at h .
Honeymoon Period
W ithi n d a ys o r we e ks a f te r t he in i ti al di a gn os is , m a n y p a ti e nt s wi t h t yp e 1 d ia be t es e xp e r ie n ce
a n ap p ar e nt r em is si on , wh i c h is re f le c te d b y d ec r e a se d b lo o d g lu co se con c en t r at i on s a nd
m a rk e dl y d ec r ea se d i ns ul i n r e qu i re me n ts . Th is i s c a ll ed t he ho n ey mo on per i o d b ec au se i t ma y
l a st f or on l y a f e w we e k s t o m o nt hs . O nc e h yp e rgl yc em i a, me t ab ol ic ac id os is , an d k et os is
r e s ol ve , e n do g en ou s i nsu l in se c re t i o n r ec o ve rs te m po r a ri l y (s e e F ig . 5 0 -1 ) . A lt h ou gh t he
h o n e ym o on pe r io d m a y la s t f o r u p t o a ye a r, in c re a si n g e xo g e no u s i ns ul in r e qu i re me n ts ar e
i n e vi ta bl e a n d s ho ul d b e a n ti ci p at e d. D u ri n g t hi s t i me , pa ti e nt s s ho u ld be m a in t ai ne d o n i n su li n
e ve n if t he do se is ve r y lo w, b e c au se in t er r u pt e d t r e a tm en t i s a s s oc ia t ed wi t h a g re a te r
i n ci de n ce of r es is ta nc e an d al le r g y t o i ns ul in (s e e Q u e st i on 25 ) .
Type 2 Diabetes
Pathogenesis: Metabolic Syndrome (Insulin Resistance
Syndrome, Syndrome X)
I m pa i r ed i n su li n s ec r et i on a nd r es is ta nc e to th e ac t io n o f i n su li n , r a th e r t ha n an ab so l ut e
i n su li n d e fi ci e nc y, c h a rac t e ri ze pa t ie n ts wi t h t ype 2 d i ab e te s. I n t he p re se n ce of in su l in
r e s is ta nc e , g lu co se u ti li za t i on b y ti ss ue s is im pa i re d , h e pa t ic g l uc os e o u tpu t o r p r od uc t io n i s
i n c re as ed , an d e xc e s s g lu c os e a cc um ul a te s i n t he ci r cu l at i on . Th is h yp e rg l yc em ia s t im ul a t e s
t h e p a nc r ea s t o p r od uc e m o r e i ns ul in in an ef f o r t t o o ve rc om e t h e i ns ul in re s is ta nc e . Th e
s im u lt a ne o us e l e vat i on of b o th gl uc os e a n d in s ul in is st r on g l y s u gg es t i ve o f in su l in re si s ta nc e .
Typ e 2 d ia b et es is ass o ci a t ed wi t h a va r ie t y o f d is o r de r s, in cl u di ng ob es i ty, a t h er o sc le r os is ,
h yp e r li p id em ia , an d h ype r t e ns io n ( F ig . 50 - 2 ). D r . G e r a ld R ea ve n , wh o re fe r s t o th is ass o ci at i on
a s s yn d ro me X , i ns u li n re s is ta nc e s yn d r o me, o r me t a b ol ic s yn d r o me , p rop o se d t h at ei t he r t he
i n su li n re si s ta nc e i ts e lf , o r t he c o mp en sa t o r y h ype r i ns ul i ne mi a t h at r es ul ts f ro m i ns ul i n
r e s is ta nc e , m a y b e th e fu n d am en t al un de r l yi ng pa t h op h ysi o lo gi c p r oc es s r e s po ns ib l e f o r t he
f r e q ue n t oc cu r r en c e o f th e se c o nd i ti o ns i n t h e sa m e p at i en t . 1 2 H o we ve r , t h e c on ce p t o f a
s i ng le de f ec t e xp l a i n in g t h is cl us t er o f d is o rd e rs is t he s u bj ec t o f c o ns id e ra b le de b a te an d
r e s ea r ch ac ti vi t y. G e ne tic as we l l a s e n vi ro nm e nta l fa c to rs su ch as c e nt r al o be si t y, s e de n ta r y
l i f es t yle s , a nd in ge s ti on o f ca lo r ic a ll y d en se fo o ds co n t ri bu t e t o t h e d e velo p me n t o f i ns ul i n
r e s is ta nc e . Me t a bo li c s yn d r om e i s co mm on in t he U n it e d S t a te s, an d b eca u se it is hi gh l y
c o r re l at e d wi t h c a r di o vas cu l a r e ve nt s , t he N a ti ona l C ho l es te r ol E du ca t io n P r o g ra m ( N C E P ) ha s
s u gg es t ed cr i te r i a f o r i ts d i ag no si s a n d t r ea tm e nt t o pr e ve nt ca r di o va sc ula r e ve nt s a nd
d i ab e te s . 1 3 Th e es t im a te d p re va le nc e of m e ta b ol i c s ynd r om e i n a d ul ts >2 0 ye a rs o l d is >2 0 %
a n d > 4 0% in ad ul t s 6 0 t o 6 9 yea r s o f a g e. 1 4 N o t a l l i nd i vi du al s wi t h me t ab o li c s yn d ro me
p r o g re ss to I G T o r d i ab et e s , b ut th o se wh o do
P . 5 0 -6
m a y be ge n e ti ca ll y p r ed is p os ed t o β - ce ll f ai lu r e . P e o pl e wi t h t yp e 2 di a bet e s h a ve a s t r on g e r
f a mi l y hi s to r y o f d ia be t es t ha n d o t h os e wi t h t ype 1 d i ab e te s. C i rc ul a ti n g I C A s a r e a bs e nt , a n d
t h e r e is no as so ci a ti on wi t h h um a n l ymp h oc yt e a nt i g en ( H L A) t yp es . 5 , 1 5
View Figure
FIGURE 50-2 Metabolic syndrome (insulin resistance
syndrome, syndrome X). Genetic and environmental
factors (visceral obesity, sedentary lifestyle, aging)
predispose some individuals to insulin resistance. To
overcome the resistance, the pancreas secretes more insulin,
leading to hyperinsulinemia. People with insulin resistance
and hyperinsulinemia commonly develop a cluster of
medical problems and biochemical abnormalities:
cardiovascular disease, hypertension, dyslipidemia,
hyperuricemia, and type 2 diabetes mellitus. Only those
individuals who are further genetically predisposed to β-cell
failure go on to develop impaired glucose tolerance and
diabetes mellitus. Many people with type 2 diabetes already
have evidence of cardiovascular disease at the time of
diabetes diagnosis. The cause-and effect-relationships
between insulin resistance and/or hyperinsulinemia and
these clinical conditions has not been clarified. See text for
expanded discussion. DM, diabetes mellitus; HTN,
hypertension; IFG, impaired fasting glucose; IGT, impaired
glucose tolerance.
P a t i en ts wi t h t ype 2 d ia be t es e xh i b it va r yi ng de g re e s o f t is su e re si st a nc e t o in su l in , i mp a ir e d
i n su li n s ec r e ti on , an d i nc r e as ed ba sa l h e pa t ic g lu c os e p r od uc t io n . S u bc la ss i fi ca t io ns o f t he se
p a t ie n ts h a ve b e en su gge s te d b a se d o n we ig h t , a g e o f o ns e t , a nd in su li n l e ve ls . Th e mo st
c om mo n l y u s ed di vi si on o f t hi s cl as s o f d i ab e ti c p a t ie n ts i s b as ed o n we i g h t o r ag e a t
d i ag n os is .
Nonobese Type 2 Diabetes
Th i s g ro u p co mp r is es app r o xi m a t el y 1 0% of th e typ e 2 d i ab e ti c p op u la t ion . Typ i c al l y, t h e y
d e ve l op a mi ld f o rm o f d ia b e te s d u ri ng ch il d ho o d, a d ol es ce nc e , o r a s youn g ad ul t s ( us u al l y
b e f o re ag e 2 5 ), a nd th e ir i ns u li n l e vel s a r e l o w i n r e s po ns e t o a gl uc os e ch a ll e ng e . I nc lu d ed in
t h is g ro u p a re pa t ie n ts wh o m a y ac t ua ll y h a ve l a te - o ns e t t yp e 1 di ab e te s 16 o r m at u r it y - o ns e t
d i ab e te s o f th e you n g ( MO D Y) . 5 Th i s f o rm of di a be t es is ass oc i at e d wi t h a s t ro n g f am il y
h i st o r y th a t s ug g es ts an a u t os om al - do mi n an t t ra ns mi ss io n . Th e u nd e rl yi n g d e fe c t is
h e t e ro ge n eo us , bu t m a y b e r el a te d t o a de f ec t i n g l uc ok i na se in s om e fa mi l ie s ( i .e . , t h e
“ g l uc os e s en so r ” i n th e β - c e ll s) . A t p r es en t at i on , s ym p to ms m a y be m o de ra t e to s e ve r e, wi t h o r
wi t h o u t k e to si s; ho we ve r , u nl ik e t yp e 1 d ia be t es , t h e d is e as e g en e r al l y i s m i ld an d c on t r ol le d
e a si l y wi t h l o w d o se s o f i n su li n (< 4 0 u ni ts ) , di et , o r o ra l a g en ts . Ma n y i n divi d u al s wi t h MO D Y
m a y be cl as si f ie d e r r on eo u sl y as h a vin g t yp e 1 dia b e te s b as ed on ag e a t o n se t . Mi l d d ia b et es
t h a t i s co n t ro ll e d e as il y in a you n g a du l t wh o h as a st r on g fa mi l y hi st o r y of d ia b et es is s t r on gl y
s u gg es t i ve o f MO D Y.
Obese Type 2 Diabetes
O b e s e i nd i vid u al s co n st it u t e t h e ma j or i t y of th e di a be t ic po p u l at i on an d 60 % to 90 % o f th e t yp e
2 d ia be t ic po p ul a ti on . Al th o u gh t ype 2 is t he m os t c om mo n f o rm of di a be t es , it s p at h og e ne si s
i s th e l ea s t u nd e rs t oo d . A s no t ed , pa t ie n ts wi t h typ e 2 d i ab e te s h a ve d e fe c ts in in su li n
s ec r e ti o n, ti ss u e r es p ons i ve ne ss to in su li n , a n d h e p at ic gl uc os e p r o du ct io n . 5
Impaired Insulin Secretion
B a s al le ve ls of in su l in are t yp ic al l y no r ma l o r el eva t e d a t di ag n os is i n th is po p ul a ti o n. Fi r st - o r
e a r l y - ph as e i ns u li n r e le as e i n re sp o ns e t o g lu co se o f te n i s r ed u ce d , a nd p u ls a ti le in su l in
s ec r e ti o n is ab se n t . O ve r t im e , t h e β ce ll co n ti nuo u sl y l o s es i t s a bi li t y t o r e s po nd t o e le va t ed
g l uc os e c on ce n t ra t io ns , le a di n g t o i nc r ea si n g l oss o f gl uc os e c on t r ol . I n a l a r ge co ho r t o f
n e wl y d i a gn os e d t yp e 2 p a t ie n ts ra n do ml y as si g ne d to va r io us t re a tm en t s, A 1 C de t e ri o ra t e d a t
t h e ra t e o f 0 . 2% to 0 .3 % p e r ye ar . 2 2 I n p at i en ts wi t h s e ve re h ype r g l yc em i a, t h e am o un t o f
i n su li n s ec r e te d i n r es p on s e t o g lu co s e is di mi ni sh e d (g lu co se t o xi c it y) .
Tissue Resistance
Mo s t p a t ie n ts a ls o e xh i b it d ec r ea se d ti ss ue r es pon s i ven es s t o i ns u li n. I nc re a si n g e vi de nc e
s u gg es t s t ha t d e cr e as e d p e ri p he r al gl u co se up t ak e a n d u ti l i zat i on in m usc l e is t he pr im a r y si t e
o f in su l in re si s ta nc e a n d r e su l ts i n p r o lo ng e d p ost p r a nd ia l h yp e r gl yc em ia . R e si s ta nc e m a y be
s ec o nd a r y to de c re as e d n u mb e rs of in su l in re c ept o r s o n t he ce ll su r f ac e, d e c re as e d a ff i ni t y o f
r e c ep t or s f o r i ns u li n , o r d e f ec ts in in su li n s ig n al in g an d a ct i on th a t f o ll o ws r ec ep t o r b in di n g.
D e f e ct s i n i ns ul in si gn a lin g an d a ct i on a re r ef e r red t o a s p os t re ce p to r o r po s tb i nd in g de f ec ts
a n d a r e l ik el y t o b e t h e pr i m ar y s it es o f in s ul in r es is t an ce . Th e p r ec is e n at u r e o f th es e d e fe ct s
i s th e f oc us o f i nt e ns e r es e a rc h.
Hepatic Glucose Production
Mo s t p e op l e wi t h t yp e 2 d i ab e te s a ls o e xh i b i t i ncr e a se d h ep a ti c g lu c os e p r o du c ti on
( g l yc og en o l ysi s a nd gl uco n e og en es is ) , wh i ch is re f l ec te d b y a n e le va t e d fa s ti n g p la sm a o r
b l oo d g l uc os e c on ce n t rat i o n. As no t e d p re vi o us l y, h ep a ti c g lu co se p ro d uct i o n is th e pr im a r y
s o u rc e o f g lu co se in t he f a s ti ng st a te . Be ca u se ins u li n n o rm al l y su pp r es ses he p at ic gl uc o se
p r o du c ti on , th is ph e no me n o n r e fl ec ts de c re as e d r e s po ns i ve ne ss o f th e l i ve r t o t hi s a ct i on .
O n e ca n i ma g in e t h e f ol lo wi n g sc en a r io i n a p er so n ge n et ic a ll y p ro n e t o in s ul in r es is t an ce an d
d i ab e te s . O ve r e a ti ng st im u la t es s ec r e ti on o f l ar ge am o un ts o f i ns ul in . Th is h ype r i ns ul in em i a, in
t u r n , p r om ot es li p og en e si s a n d d o wn - r eg u la t es , or d ec r ea s es , t he n um be r o f i n su li n re ce p to r s
o n th e s u rf a ce of th e ta rg e t o r g an . Th is l e ad s t o i n su li n re si s ta nc e a nd , wh e n t h e p an c re as is
u n a bl e t o s ec r et e s u ff ic ie n t i ns u li n t o o ve r co me ti ss u e r es is t an ce , h ype r glyc e mi a . Hi g h - g lu co se
c o nc en t r at i on s a r e t o xi c t o t he β -c e ll s a nd pe r ip he r a l t is su es , l e ad i ng to fu r t h er de t e ri o ra t io n
o f in su l in s ec r e ti o n a nd re s is ta nc e to in su li n a c ti on . Th u s, th e o b es e p a ti en t wi t h di ab e te s
o f t en is i n a vi ci o us c yc le t ha t c a n b e b r ok en on ly t h r o ug h d ec r e as ed c a lo r i c in t ak e , we i g h t
l o ss , a nd e xe r c is e .
Clinical Presentation
Typ e 2 d ia b et es is t ypi cal l y d ia gn os e d i nc id e nt a lly d u r i ng a r ou t in e p h ys ica l e xa m in a ti on o r
wh e n t h e p a ti en t s e eks at t e n ti on f or an o th e r c omp l ai n t . Th i s is be c au se sym p t om s a r e so mi ld
a n d t h ei r on se t s o g r ad ua l th a t t h e y c an ea si l y be “ e xp l a in e d a wa y. ” W hen g i vin g a hi st o r y of
t h e ir il l ne ss , p e op le wi t h t yp e 2 d ia be t es ack n o wle d g e f at i gu e , p ol yu r ia , an d po l ydi p si a .
B e c au se th e se pa ti e n ts h a ve s u f fi ci en t in su li n c on c en t r at i on s t o p r e ven t l ip o l ysi s, t he r e is
u s ua ll y n o h is t o r y o f k e to s is e xc e p t in s i tu a ti o ns o f un us u al s t r es s ( e .g . , in f ec t io ns , t ra um a ) .
F u r t he r mo r e, we i g h t l oss i s u nc om mo n i n t h es e i nd i vi du a ls b e ca us e re la t i ve l y h ig h e n do ge n ou s
i n su li n l e ve ls p r om o te li po g e ne si s. C om mo nl y, mac r o vas cu l a r d is ea se is evi d e n t a t t h e t im e o f
d i ag n os is ; o cc as io n al l y, m ic r o vas cu l a r co mp l ic at io n s t ha t s u gg es t th e p r es e nc e o f
u n di a gn os e d o r s ub cl i ni ca l di ab e te s f o r 7 to 10 ye a r s a re e vi de n t as we l l . B e ca us e t ype 2
d i ab e te s p a ti e nt s r e ta i n s om e p a nc r ea t ic re se r ve a t th e t im e o f di ag n os is , t h e y ge ne r a ll y ca n
b e t re a te d wi t h d ie t , e xe r c is e , a nd o ra l a n ti di a be ti c m ed ic a ti o ns fo r s e ve ra l ye a rs .
N e ve r t h el es s, ma n y e ven t u al l y r eq ui r e i ns ul i n f or c on t r ol of th e i r s ymp t om s .
Gestational Diabetes Mellitus
G e s t at i on a l di a be t es m e ll i t us ( G D M) a f f ec ts ab o ut 7 % o f a ll p re g na nc i es an d is d e fi n ed as “a n y
c a r bo h yd r a t e i n to le r a nc e wi t h o ns e t o r f i rs t re co gn i t io n d u ri n g p re g na nc y. ” 5 , 1 7 Th e on s et of
d i ab e te s d u ri n g p r eg na nc y a nd i ts d u r at i on af f ec t t h e p r og n os is fo r a go od o bs te t r ic a n d
p e r in a ta l o u tc om e . S e e C h a p te r 46 , O bs te t r ic s.
P . 5 0 -7
Diagnosis
Diagnostic Criteria
I n 19 9 7, t he di ag n os ti c cr i t e ri a f o r d i ab e te s me l li tu s we r e m od i fi e d b y an E xp e r t C o m mi t te e o f
t h e Am e ri ca n Di a be t es As so ci a ti o n ( Ta b l e 5 0 - 2 ) .5 , 1 8 Fo r n o np r e gn an t in divi d u al s o f a n y ag e , a
d i ag n os is of di a be t es c an b e ma d e wh e n on e o f th e fo l lo wi n g i s p r es en t :

C l a ss ic s i gn s a nd s ym p to ms o f d ia be t es ( po l yu ria , po l yd ip si a , ke t on u r ia , a n d ra pi d
we i g h t lo ss ) c om bi n ed wi t h a r an d om p l asm a g l uc os e ≥ 20 0 m g/ d L.

A f a st in g p l as ma gl uc ose ( F P G ) ≥ 12 6 m g/ d L.

F o l lo wi n g a st a nd a rd o ral g lu co se c h al l en ge ( 75 g g lu co se fo r an ad u lt o r 1 . 75 g /k g f o r
a ch i ld ) , t h e ve n ou s p la sm a g l uc os e c on ce n t ra ti on is ≥ 20 0 m g /d L a t 2 ho ur s an d > 2 00
m g /d L a t le as t o n e o th e r t im e du r in g t h e t es t (0 . 5, 1 , 1 . 5 h ou r s ); th is is the o r al gl uc os e
t o l er a nc e t es t ( O G TT) .
Th e d i ag no si s m us t b e co n f ir m ed o n a su bs e qu en t da y b y a n y o n e o f t h e a f o r em en t io ne d
c o nd i ti on s i n t h e a bs en ce o f u ne q ui vo ca l h yp e r glyc e mi a wi t h a cu t e me t a bo l ic c om p li ca t io ns .
I n d i vid ua ls wi t h F P G valu e s o r O G TT va l u e s t h at a r e i n te r me di a te be t we e n n o rm al an d t h os e
c o ns id e re d d i ag n os ti c o f d i ab e te s a r e co ns i de r ed t o ha ve IF G o r I G T. Th es e i n di vi du a ls ar e n o t
g i ve n t h e d ia g no si s o f d ia b e te s b ec au se o f b r oa d s oc ia l , p s yc h ol o gi ca l, an d ec on om ic
i m pl ic a ti on s . Th e ca t eg o ri e s o f F P G va lu e s a re as f o ll o ws :

A n o rm al F P G i s < 1 00 mg / d L. I n 2 00 3 , t hi s va l ue wa s l o we r e d f r om 11 0 mg / d L. 1 8

A n F P G 10 0 –1 25 mg / d L is I F G .

A n F P G ≥ 12 6 m g /d L i nd ic a te s a p ro vi si on a l d ia gno s is o f di ab e te s t h at mus t be
c o nf i rm e d, as de sc ri b ed p r e vi ou sl y.
Th e c o r re sp o nd in g c a te go r i es wh e n t h e O G TT i s u s ed fo r di a gn os is a re as f ol lo ws :

A 2 - ho u r p os t lo a d g lu co se ( 2 -h P G ) < 14 0 m g/ d L i nd i ca t es n o rm a l g lu co se to l e ra nc e .

A 2 - h P G ≥ 14 0 m g/ d L a nd < 20 0 m g /d L i nd ic a te s IG T.

A 2 - h P G ≥ 20 0 m g/ d L i ndi c at es a p r ov is io n al di agn o si s o f d ia b et es , wh i ch m us t be
c o nf i rm e d b y a s ec on d te s t .
Ma n y f a c t o rs ca n i mp ai r g l uc os e t o le r an c e o r i nc re a se pl as ma gl uc os e , a nd t he se mu st be
e xc l u d e d b ef o r e a f i rm dia g n os is o f d i ab e te s i s ma d e . F o r e xa m p le , a n i n di vi d ua l wh o ha s n ot
f a s te d f o r a m i ni mu m o f 8 h ou r s ma y h a ve a n e leva t e d F P G ; o ne wh o ha s f a st e d t oo lo n g ( > 16
h o u rs ) o r ha s i ng es t ed ins u f fi ci en t c a rb o h yd ra t es b e f o re te st i ng m a y h a ve a n I G T. P a ti en t s
wh o a r e te s te d f o r g lu c os e to le r a nc e d u ri ng , or so o n a f te r , a n a c ut e i ll n ess ( e. g . , a m yo ca r di a l
i n f ar c ti o n [ MI ] ) m a y b e mi s di ag n os ed be ca u se of th e p re se nc e o f h i gh c o nc e nt r a ti o ns o f
c o un t e r- r e gu la t o r y ho r mo n es th a t i nc r ea se gl uc os e c on c en t ra t io ns ; gl uc os e to le r a nc e o f te n
r e t u rn s t o n o rm a l in t he se i nd i vid u al s. P r eg n an c y, m an y f o rms o f s tr es s , an d la ck o f ph ys ic al
a c ti vi t y ca n a f f ec t t he glu c os e t ol e r an ce s im i la r l y. Ma n y d r u g s ma y a lt e r gl u co se to l e ra nc e d u e
t o t he i r e f fe ct s o n i ns ul i n r e le a se an d t is su e re spo n se to in su l in , a s we ll as t hr o ug h d i re c t
c yt o t o xi c e f f ec ts on th e p a nc r ea s . Th e se a re di sc us s ed i n m o re de t ai l l a te r in t hi s ch a pt e r .
D r u g s a nd ot h e r ch em ic al s a ls o m a y fa ls e l y e l e vat e t he pl as ma gl uc os e c on c en t r at i on s t h ro u gh
i n t er f e re nc e wi t h s pe ci f ic an a l yti c m et h od s.
Table 50-2 Normal and Diabetic Plasmaa Glucose Levels in mg/dL (mmol/L) for the Oral
Glucose Tolerance Test
Fasting
½, 1, 1½ hr
2 hr
Normal
<100 (5.6)
<200 (11)
<140 (7.8)
Impaired glucose tolerance
<126 (7.0)
≥200 (11)
140–200
(7.8–11)
Impaired fasting glucose
100–125
(6.1–7.0)
Diabetes (nonpregnant adult)
≥126 (7.0)
≥200 (11)
≥200 (11)
a
Equivalent venous whole blood glucose concentrations are approximately 12% to 15%
lower. Arterial samples are higher than venous samples postprandially because glucose has
not yet been removed from peripheral tissues. Capillary whole blood samples contain a
mixture of arterial and venous blood. Fasting levels will be equivalent to whole blood
venous samples. One hour after a 100-g glucose load, capillary samples may be 30 to 40
mg/dL higher than venous samples.
Type 1 or Type 2 Diabetes Mellitus?
A t t im es it m a y b e d if f ic ul t to cl as si f y pa t ie n ts as h a vi n g t yp e 1 o r t yp e 2 di a be t es m e ll i tu s.
G e n e r al l y, i f a p at ie n t i s yo u n g er t ha n 3 0 yea r s o f a g e, is l e an , an d h as s ig n s a nd s ym p to ms of
d i ab e te s m el li t us c om b ine d wi t h a n e l e vat e d F P G, t yp e 1 di a be t es i s l ik ely a n d th e p a ti en t
s h ou l d b e t r ea t ed wi t h i ns u li n . A l th o ug h t h e p re se n ce of mo d er a te ke t on ur i a wi t h
h yp e r gl yc em i a in an o the r wi s e un st r es se d p a ti e nt s t ro ng l y su p po r ts th e d ia g n os is o f t ype 1
d i ab e te s , i ts ab se nc e i s n o t o f di ag n os ti c val ue . H o we ve r , r e l at i ve l y l e an o l de r ad u lt s i ni t ia ll y
p r e se n ti ng wi t h wh a t a p pe a r s t o b e t yp e 2 di a be te s b ec a us e t h e y a r e re sp o ns i ve t o o r a l a ge n ts
o r lo w d o s es o f in su li n ma y b e d is c o ver e d s ub se qu e n tl y as ha vi n g t yp e 1 d i ab e te s . Th e
p r e se nc e o f a n ti b od ie s to is l et ce ll co mp on e nt s m a y in d ic at e th e n ee d for e ve n tu a l i ns ul in
t h e r ap y. 1 6 C o n ve rs el y, cl i ni ci a ns a r e b e gi nn i ng to o bs e r ve mo r e c as es of t yp e 2 d ia be t es in
o b es e c hi l dr e n. 1 9 P r es en t l y, 8% to 45 % o f c hi l d re n wi t h n e wl y d i ag n os ed d i ab e te s h a ve t yp e 2
d i se as e . Th e s e cl in ic a l ob s e r vat i on s e xp l a i n wh y t h e m ed ic a l co mm u ni t y is ab a nd o ni ng t he
t e r ms a d ul t - on se t d i ab e te s , y ou t h -o ns e t d ia be t es , a nd no n –i ns u li n -d e pe nd e n t d ia b et es
me l l i tu s.
Long-Term Complications and Their Relation to Glucose
Control
Th e l o ng e r -t e rm se qu e lae o f d ia b et es ac co u nt fo r m os t o f th e m o rb id i t y and mo r t al i t y i n th e
d i ab e ti c p o pu la t io n . Th e m a na g em en t o f s e le ct e d c om pl ic a ti o ns o f di ab e tes me ll i tu s i s
c o ns id e re d l a te r in th is ch a p te r . He r e , we s im p l y p r o vi de an
P . 5 0 -8
o ve r vi e w o f t he t ype s o f c om p li ca t io ns th a t t yp ic al l y d e vel op in pe o pl e wi th t yp e 1 an d t yp e 2
d i ab e te s . C o mp li ca t io ns a r e t ypi ca l l y a ss ig n ed to m ac r o vas cu la r o r mi c rova s c ul a r
c om p li ca t io ns . Di a be t es m e ll i tu s is on e o f m a n y ri sk f ac to r s f o r m ac ro va sc u la r di se as e
( c a rd i o vas cu la r di se as e , s t ro k e, pe r ip h e ra l vasc ul a r d is e as e ), bu t th es e ris k f ac t o rs te n d t o
c l us te r in pe o pl e p r on e to t yp e 2 di ab e te s . A s d isc us s ed m o re f ul l y in s u bs e qu e nt se ct i on s,
g l uc os e t o xi c i t y ap p ea rs t o co n tr i bu t e mo s t t o t h e d e ve lo pm e nt an d p r o gr es si o n o f
m ic r o vas cu l a r co mp l ic at io n s, wh i c h i nc lu de r et i nop a t h y, n ep h r op a th y, an d n e u ro p at h y.
H o we ve r , e p id em i ol og ic s t ud i es a ls o s h o w a g e ne r a l r e la t io ns hi p b e t we en d eg r ee o f g lu co se
c o nt r o l a nd ri sk fo r c a r dio va s cu la r e ven t s. 2 0 Th us , th e p r im a r y go al f or bo t h t ype 1 a nd t ype 2
d i ab e ti c i nd i vi du a ls i s t o b r i ng gl uc os e c o nc en t ra ti o ns as c lo s e t o n o rm al va l ue s a s p os si bl e .
R e s ul t s o f t he D ia b e te s C o m pl ic a ti o ns a n d C o nt ro l Tr i al ( D C C T) d e fi ni t i ve l y es t ab l is he d t h at
i n t en si ve t re a tm en t of t yp e 1 d ia b et es c a n p r e ven t o r sl o w t h e o ns e t o f l on g - t er m d ia b et e s
c om p li ca t io ns , i nc l ud i ng r e t in o pa t h y, n e ph r op a th y, a nd ne u r op a th y. 2 1 Th e D C C T wa s a
m u lt ic e nt e r , r a nd om i ze d s t ud y o f 1 , 44 1 n e wl y d i ag n os e d t yp e 1 di ab e ti c pa t i en ts ag es 13 t o 3 9
ye a r s th a t wa s de si g ne d t o de t e rm in e wh e th e r t h e c om pl ic a ti o ns o f di ab e tes co ul d b e re d uc ed
o r p re ve n t ed wi t h i n te n s ive i ns u li n t h e ra p y ai me d a t ac hi e vin g e u gl yc em ia. P a ti e nt s we r e
r a n do mi ze d to r ec ei ve co n ve n ti o na l o r i n te ns i ve i n su li n th e ra p y an d we r e f o ll o we d fo r a me a n
o f 6 .5 ye ar s . P a ti e nt s i n t h e c on ve n ti o na l t r e at men t g ro u p r ec ei ve d on e t o t wo i n su li n
i n je c ti on s p e r d a y, p e r for m e d d ai l y bl oo d g l uc os e m on i to r in g , a n d r e tu r ned t o c li ni c e ve r y 3
m o nt hs . P at i en ts in th e in t e ns i ve t r ea t me n t g ro u p we r e i n it i at e d o n i ns ul in i n t h e h os pi t al . Th e y
we r e g i ve n t h r ee or mo re i ns ul in in j ec ti o ns p e r da y o r us ed an in su l in pum p . Th e y p e r fo r me d
b l oo d g l uc os e t es t s f ou r o r mo r e t im es pe r da y an d ha d we ek l y t o mo n th ly c l in ic vi si ts . A
h e al t h c a re te am p ro vi d ed e xt e n si ve e du ca t io n a nd co ac h in g t o th e i n te ns ive l y t r e at e d g r ou p
t h r o ug ho u t t h e s tu d y.
I n t en si ve t re a tm e nt r ed uc e d t he r is k o f cl i ni ca ll y m e an i ng f ul re t in o pa t h y, n e p hr o pa t h y, a n d
n e u ro p at h y b y ap p ro xi m a t e l y 6 0 %. Th u s, pa t ie n ts t re a te d wi t h i n te ns i ve th e r ap y e xp e r i e nc ed a
s i gn i fi ca n t d ec r ea se in th e in ci de n ce of lo n g - t e rm mi cr o va sc ul a r c om pl ica t i on s.
Th e e f f ec t o f t i gh t b l oo d g l uc os e c on t r ol on th e ca r d io va sc ul a r a n d mi c rova s c ul a r co mp l ic at i on s
o f t yp e 2 d i ab e te s wa s ad d r es se d b y t he U n it e d K i n gd om P r os pe c ti ve D ia b e te s S t ud y
( U K P D S ) . 2 2 O ve r a 10 - ye a r pe r io d , 3 ,8 6 7 n e wl y d i ag n os ed t yp e 2 d i ab e tic s wi t ho u t
c om p li ca t io ns we r e r an do m l y a ss ig n ed t o a n in t en s i ve t r ea t me n t g ro u p u si n g a s u lf o n ylu r ea
( g l ip i zi de , c hl o rp r o pa mi de , o r g l ybu r id e ) o r in su lin o r m et f o rm in ( if ob es e ), o r to a co n ve nt i on a l
t r e a tm en t g r o up us in g d ie t . Th e g o al fo r th e i n te ns i ve tr e at m en t g r ou p wa s a F P G < 10 8 m g/ d L
ve r s us a F P G < 27 0 m g/ dL i n t he co n ven t io n al t rea t me n t g r ou p . D r u g t h era p y co u ld be ad d ed in
t h e d i et - t r ea t ed gr o up if h yp e r gl yc em ic s ym p to ms o cc u r re d o r to at t ai n a FP G < 2 7 0 mg / dL .
E n d po i nt s i nc lu d ed di a be t es - r el a te d c om p li ca ti on s , d ia b et es - r el a te d de at h s , a nd al l -c au se
m o r ta li t y.
H e m og l ob in A 1 c ( A 1 C ) valu e s we r e 7 .0 % i n th e i n te n si ve t re a tm en t gr o up ve r s us 7 . 9% in th e
c o n ven t io n al gr o up . Th e re we r e n o d if f e re nc es in A 1 C va l ue s a mo ng t he t re a tm e nt a rm s i n t he
i n t en si ve t re a tm en t gr o up . B y t he en d o f th e s tu dy, 8 0 % o f p a ti e nt s i n t he d i et g ro u p r eq u i re d
p h a rm ac ol o gi c t he r a p y to me e t t r ea t me n t g oa ls , a n d i n ves t ig a to r s we r e un a bl e to m a in t ai n t h e
i n t en si ve t re a tm en t go al wi t h m on o th e r ap y o r a sin g le da i l y d o se of ul t r al en t e i ns u li n .
C o n se q ue n tl y, ma n y pa t ie n ts e ve nt u al l y we r e t rea t e d wi t h co mb i na ti o n t he r a p y. Us in g a n
i n t en t - to - t re a t a na l ysi s in t he in t en si ve t re a tm e nt g r o up , t h e r is k o f d i ab e te s - re l at e d e nd p oi n ts
wa s 1 2 % l o we r ( P < . 00 29 ) , di a be t es - re l at e d d ea th wa s 1 0% l o we r ( P < . 34 ) , an d a ll - ca us e
m o r ta li t y wa s 6 % l o we r ( P < . 44 ) c om p ar e d wi t h co n ve n ti o na l t h er a p y. Th e r i sk o f
h yp o g l yc em i a a nd we i g ht g ai n wa s s ig ni f ic an t l y hi g he r in th e i n te n si ve t rea t me n t g r ou p . ( N o te :
m e t fo rm i n a na l ysi s wa s th e s u bj ec t o f a se p a ra t e s t ud y. )
Th e o ve r a ll m ic r o vas cu l ar c om pl ic a ti o n r a te wa s d e c re as e d b y 25 % i n t h e i n te ns i ve tr e at me n t
g r o up . E pi de mi o lo gi c a na l ys is o f th e d a ta f ro m UK P D S d em o ns t ra t ed a c on t i nu ou s re la t io ns h ip
b e t we e n th e r is ks of mi cr o va sc u la r c om p li ca t io ns a n d g l yc em i a, su ch th a t f o r e ve r y p e rc en t ag e
p o in t r ed uc t io n i n A 1 C , t he r e wa s a 35 % re d uc ti o n i n t h e r is k o f c om pl ic a tio n s. W het he r
i n t en si ve th e r ap y d es ig ne d to a tt a in s us t ai n ed nor m o gl yc em ia de c re as es th e ri sk of
m ac r o vas cu l a r d is ea se wa s l e ss c le a r . I n t h e U KP D S , a 16 % r e du ct i on in t h e r is k o f c om bi n ed
f a t al o r n on f at a l MI a n d s u dd e n d ea t h wa s o bs erve d , wh i c h f ai le d to r ea ch s ta t is ti ca l
s i gn i fi ca nc e ( P = . 0 52 ) . Th i s is su e i s d isc us se d m o r e f ul l y in Q u es ti o n 46 .
O t h e r s t ud i es s up p o rt the us e o f a mo r e c om p re he n si ve ap p ro a ch to p re ve n t in g m ic r o vasc u la r
a n d m ac r o vas cu la r c om pl i ca t io ns in pa t ie n ts wi t h t yp e 2 d ia b et es , es pe ci al l y si nc e c o ro n a r y
h e a r t d is ea se is th e l ea di n g c au se of p re ma t u re de a t h i n t hi s g r ou p . I n a UK P D S g r ou p
s u bs tu d y, ti g ht bl o od c on t r ol ( <1 3 0 /8 5 mm H g ) re d uc e d t he r isk o f st r ok e b y 4 4% ( P = . 01 3 )
a n d m ic r o vasc u la r en dp oi n ts b y 37 % ( P = . 0 09 2 ) . 2 2 Th e St e no g ro u p f ou nd t ha t m u lt i fa ct o r ia l
i n t en si ve t re a tm en t of pat i e nt s wi t h t yp e 2 di ab e te s a n d mi c ro a lb um in u r a f o r a me a n o f 7 . 8
ye a r s re d uc ed b y 5 0 % t he r is k o f c a rd io va sc ul a r a n d m ic r o vasc u la r e ven ts co mp a re d wi t h
p a t ie n ts tr e at e d c on ve n tio n al l y ac co r di n g t o Da n is h g u id el i ne s . Th e i r i nt e rve n t i on s i nc lu d ed
l i f es t yle ed uc a ti o n a nd ag g r es si ve us e o f d r ug s to ac h ie ve a l o we r bl o od p r e ss u re , A 1 C , an d a
n o r ma l l ip i d p ro f il e . 2 3 Se e Ta b le 50 - 11 f or t he co m po n en ts o f in t en si ve in s ul in t he r ap y.
Screening for Type 2 Diabetes
Th e A D A a d vis es ag ai n st r o ut i ne s c re e ni ng f o r t yp e 2 d ia b et es ou t si de o f t h e h e al t h ca r e
s e t ti ng be ca u se of th e l ow l i k e li ho o d o f f o ll o w - u p c a r e a nd te s ti ng in t he ca s e o f b o th ne g at i ve
a n d p os i ti ve r es ul ts . Th e F P G is t he p re f er r e d o ve r t he O G TT a s a s c re e ni n g t es t ba se d o n
c os t an d c on ve n ie nc e . Pe o pl e a g e ≥4 5 yea r s, pa rt i cu l ar l y o ve r we i gh t i n di vi d ua ls ( B MI ≥ 2 5
k g /m 2 ) s ho ul d b e te st e d e ve r y 3 ye a rs , b u t yo u nge r p at i en ts m a y b e t es ted mo r e f r e qu e nt l y if
t h e y a re o ve r we i gh t a n d h a ve on e o r m o r e o th e r ri sk f ac to r s : f am il y h is to ry o f d ia be t es ,
s e de n ta r y l if es t yl e , e th n ic p re d is po si t io n , p re vi o us I F G o r I G T, hi s to r y o f g e st a ti o na l d ia b e te s
o r ma c ro so mi a , h yp e rt e ns i on , d ys li p id em ia ( hi g h -d e ns i t y l i po p ro t ei n [ H DL ] c ho l es te r o l ≤ 3 5
m g /d L a n d t r ig l yce r id e s ≥ 2 5 0 m g /d L ), hi s to r y o f p o l yc yst ic o va r y s yn d rom e o r va sc ul a r
d i se as e . 2 4
Prevention of Type 1 and Type 2 Diabetes Mellitus
B e c au se th e c li n ic al s ymp t om s o f t yp e 1 d ia be t es m el l it us a re th e o ve r t e xp r e ss io n o f a n
i n si di o us p a t ho ge n ic p r oc es s t h at be g in s ye a rs ea r l ie r , i n ves t ig a to r s a r e fo c us in g a t te n ti o n o n
s t r at e gi es th a t a l te r th e n a t u ra l h is t or y o f th e d ise a se (s e e F ig . 5 0 - 1 ). Fi rs t - de g re e re l at i ves o f
i n di vi d ua ls wi t h t ype 1 d ia b e te s
P . 5 0 -9
m e ll i tu s h a ve a n i nc r ea se d ri sk fo r de ve l op in g the d ia be t es an d c an be ide n t if i ed b y th e
p r e se nc e o f i mm un e m a rk e rs t ha t m a y h e r al d t h e d i se as e b y m an y ye a rs . 25 Th i s h as le d t o
a t t em p ts a t i mm u ne i n t erve n t i on at t he pr e di a be te s s t ag e wi t h su c h d ru g s a s n ic o ti na mi d e a nd
l o w d o se s o f i ns u li n, b ut n e i th e r wa s f ou n d t o d ela y o r p re ve n t d ia b et es . 26 , 2 7 , 2 8 I n c on t r as t ,
t r e a tm en t o f ne wl y d i a gno s ed di a be t es wi t h a ge n ts t ha t m od i f y c yt o to xi c T - c e ll s ma y sl o w
p a nc r ea t ic de st r uc t io n an d p ro g re ss io n o f di ab e te s . 2 9
I n ad d it i on to t he 18 . 2 mi l li o n p eo pl e i n th e Un i ted S t at e s wi t h di a gn os e d a n d u n di ag n os ed
t yp e 2 d ia b et es , an ad d iti o na l 2 0 .1 mi ll i on Am e ri ca n s h a ve p r ed i ab e te s ( IG T o r I F G ) . 1 Th e
a n n ua l r is k o f p r og r es si on t o t yp e 2 di a be t es m el li t us in pe r so ns wi t h I G T i s 1 % to 5% . 7
P e r s on s a t r is k f o r I G T a n d wh o a re el ig i bl e f o r f ur t h e r sc r e en in g i nc l ud e th o se wh o a re
o ve r we i g h t , t ho se w h o ha ve a fa mi l y hi st o r y of dia b e te s, in d i vid u al s wh o h a ve a h is to r y o f
g e st a ti o na l d ia b e te s o r wh o h a ve de l i ve re d a bab y > 9 l b , a n d t ho se wi t h a me d ic al hi st o r y of a
h i gh bl o od gl uc os e te st wi t h o u t a di a gn os is o f dia b e te s.
Th e D i a be t es P re ve n ti o n P r o g ra m Re se a rc h G ro up ( D P P ) s t ud i ed pe op l e a t hi g h r is k f o r
d e ve l op in g d i ab e te s t o de t e rm i ne i f li f es t yle in t e rve n t i on s o r m e tf o rm in wo u ld p re ve n t o r d e la y
t h e o ns e t o f t ype 2 d ia bet e s . 3 0 Su bj ec t s we r e a t le a st 25 ye a rs ol d , o ve r we i gh t ( B MI ≥ 2 4 ) , a nd
h a d a F P G o f 95 to 12 5 m g /d L a n d a p l as ma gl uco s e o f 1 40 t o 1 99 m g /d L 2 h ou r s f ol l o wi ng a
7 5 - g o r al gl uc os e t o le r anc e te st . E ff o r ts we r e m ad e to en r o ll a di ve r se pop u la t io n wi t h re ga r d
t o e th ni ci t y, ag e , a nd hi st o r y o f g es t at i on al di a be te s . Pa r ti ci p an ts we r e r and o ml y as si g ne d to
o n e o f th r ee in t e r ven t io ns :

I n t en si ve li f es t y l e i nt e rve n t io n : Th i s g r ou p re ce i ve d an in t en si ve di e t a nd e xe r c i s e
p r o g ra m ( 1 50 m i nu t es / we e k ) a im ed at ac hi e vi ng a n d m ai n ta in i ng a 7 % we i g h t l oss .

Me t f o r mi n 8 50 mg B I D wi t h s t an da r d d i et an d e xer c is e : Th e an t ih yp e r gl yce m ic
b i gu a ni d e, m e t fo r mi n , wa s s el ec t e d b ec au se it im p r o ves th e m et a bo li c ab n o rm al i ti es
t h a t a cc om pa n y ob es i t y a n d I G T. 3 1 Th i s g ro u p a ls o re ce i ve d s ta nd a r d a dvi c e re g ar d in g
t h e b e ne f it s o f a he a lt h y d i e t a nd e xe r c is e.

S t a n da r d t h er a py : Th is gr o u p wa s g i ven a p la ce bo f o r me t f or mi n a n d r ec ei ve d s t an d a rd
a d vi ce on th e b e ne f it s o f a he a lt h y di e t a nd e xe r ci s e.
R e s ul t s o f t he st u d y we re d r am at ic , l e ad i ng to it s e a rl y c lo su r e . R e la t i ve to t he pl ac e bo g ro up ,
t h e i nc i de nc e o f d i ab e tes wa s r ed uc e d b y 58 % an d 31 % i n t h e i nt e ns i ve li f es t yl e a nd me t fo r mi n
g r o up s , r es p ec ti ve l y. The i nc id en c e r a te s f o r t he t h r ee g ro up s we r e 4 . 8, 7 . 8 , a nd 11 . 0 c as es
p e r 10 0 p e rs on - ye a rs , res p ec ti ve l y. A re pe a t o r al g l uc os e t ol e r an ce te s t wa s p e r fo r me d i n t h e
m e t fo rm i n g r ou p wh o h ad n ot de ve l op e d d ia be t es 1 t o 2 we e ks af t e r t he d r u g h ad be e n
d i sc on t in u ed to de t e rm ine wh e t h e r t he d r u g s im ply m a sk ed di a be t es t h r oug h it s
a n t ih yp e rg l yce mi c e f fe c ts . Th e i nc i de nc e o f d i abe t es wa s st il l re d uc ed b y 2 5 % r el a ti ve t o t he
p l ac e bo gr o up . 32 O t he r s t ud i es h a ve c o nf i rm ed th e va lu e o f l i fe s t yle in t erve n t i on 3 3 a nd ot h er
d r u gs (a c ar b os e , t r og li t azo n e ) in th e p r e ve nt i on o f t yp e 2 d i ab e te s. 3 4 , 3 5
Treatment
Th e r e a re t hr e e m aj o r com p on e nt s t o t h e t r ea tm en t o f di a be t es : d i et , d r u gs ( in su li n an d o r al
h yp o g l yc em ic o r a nt i h ype r g l yce mi c a ge n ts ) , a nd e xe r c i s e. E ac h o f t h es e c om p on e nt s i n te r ac ts
wi t h t h e o t he r s t o t he e xt e n t th a t n o as se ss me n t a n d m od i fi ca t io n o f o n e c a n b e ma d e wi t ho u t
k n o wl e dg e o f th e o t he r two . Ta r g e t bl o od gl uc ose va l ue s f o r p r eg n an t d ia b e ti cs a r e ve r y s t r ic t.
Medical Nutrition Therapy
Principles
Me d i c a l n u t ri ti o n t he r a p y p l a ys a c r uc ia l r o le in the t he r a p y o f al l i nd i vid u al s wi t h d ia b et es .
U n f o r tu n at e l y, p a ti en t acc e pt a nc e a nd ad h e re nc e t o di et is of t en po o r , b ut r e vi se d
r e c omm e nd a ti on s t h at a re e vi de nc e b as e d a nd mo r e fl e xi b l e t h an pr e vi ous ap p r oa ch es of f e r
n e w o p p o rt u ni ti e s t o i nc re a se th e e f f ec ti ve n es s of n u tr i ti o n t he r a p y. 3 6
N u t r i ti o n t he r ap y i s d es ig n e d t o h el p p a ti e nt s a ch i e ve a p pr o p ri a te m e ta bo l ic an d p h ysi o lo gi c
g o al s (e . g. , g l uc os e , li p id s , b lo o d p r ess u r e, p ro te i nu r i a, we i g ht ) , s el ec t he a l th y f oo ds , an d t o
t a ke in t o c on si de r a ti o n pe r s on al an d c ul t u ra l p r e fe r e nc es . Ap p r op r ia t e l e ve l s a nd t ype s o f
p h ys ic al ac ti vi t y t o a ch ieve a he a lt h ie r s t at u s a re i nc o r po r at e d i nt o th e p re sc r i pt i on .
Nutrition Therapy and Type 1 Diabetes Mellitus
F o r pa t ie n ts wi t h t yp e 1 d i ab e te s t ak i ng fi xe d d os es o f i ns ul in , a me a l p la n is d es i gn e d t o
p r o vi de ad e qu a te ca r bo hyd r a t es ti m ed to m a tc h th e pe ak ac ti o n o f e xo g e n o us l y ad mi n is te r ed
i n su li n . Re g ul a rl y sc h edu l ed me al s a n d sn ac ks ar e r eq u i re d t o p r e ve nt h yp o gl yc em ic r ea ct i on s.
F o r t un a te l y, n e we r i ns ul in s a n d i ns ul i n r eg im e ns p r o vi de mu ch m o r e f le xi b i li t y i n t he am ou n t
a n d t im i ng of f oo d i n ta ke. N o w, p a ti e nt s wh o a r e ta u g ht to “c o un t c a rb o h ydr a t es ” c a n i nj ec t
r a p id - o r sh o r t -a ct i ng in su l in do se s d es i gn ed t o ma t ch t he i r a nt ic i pa t ed in ta k e. I nt e gr a ti o n o f
f o o d i nt ak e , p h ysi ca l a ct ivi t y, a n d i ns ul in do se is c r i ti ca l a n d di sc us se d e xt e ns i ve l y i n th e
c as e s t h a t fo ll o w.
Nutrition Therapy and Type 2 Diabetes Mellitus
F o r pa t ie n ts wi t h t yp e 2 d i ab e te s , me a l p la ns emp h as i ze n o rm al i zi ng pl asm a g l uc os e a nd li p id
l e ve ls as we l l a s ma i nt ain i ng a n o rm al bl o od p re ss u r e ( B P ) to pr e ve n t o r m i ti g at e
c a r di o vas cu l ar mo r bi d it y. A l th o ug h we i gh t l os s r ed u ce s i ns ul i n r es is t an ce a n d i mp r o ves
g l yc em ic c o nt r ol , t ra di t ion a l d ie t a r y s t r at e gi es in co r p o ra t in g h yp oc a lo r ic die t s h a ve n o t b ee n
e f f ec t i ve i n ac h ie vi ng lo ng - t e rm we i g ht lo ss . A sus t ai n ab le we i g h t l oss o f 5 % to 7% ca n b e
a c hi e v e d wi t h i n s tr uc t u red p r og r am s t ha t e mp h as ize l i fe s t yle c h an ge s , p h ys ic a l ac t i vi t y, a nd
f o o d i nt ak e th a t mo d es tly r e d uc es ca lo r ic an d fa t i n ta ke . Ta bl e s 5 0 - 3 a n d 5 0 - 4 d es c ri be ho w t o
c a lc ul a te th e d es i r ab le bo d y we i g h t a nd es t im at e m a in t en a nc e - c al o ri e r e qu i r em en t s f o r a du l ts .
Specific Nutrition Components
Me d i c a l n u t ri ti o n t he r a p y i s a c r i ti ca l c om po ne n t o f di a be t es c a re . Fo r a m o r e e xt e n si ve
d i sc us si on o f t he p ri nc ip le s u n de r l yin g n u t ri t io n t he r a p y, t h e r e ad e r i s d ir ec t ed t o o th e r
s o u rc es . 3 6 , 37 A f e w k e y p r i nc ip l es a r e b r ie f l y no te d be lo w b e c au se th e y ar e t he c o mm on
s o u rc e o f m is un de r s ta ndi n g .
Carbohydrates and Artificial Sweeteners
C a r b o h ydr a te s i nc lu d e su g a r , st a rc h , a nd f ib e r an d th e y a re li b er a ll y i nc or p o r at e d i nt o th e d ie t
o f a p e rs on wi t h di ab e tes . In fa c t, t he am ou n t o f d i e ta r y ca r b oh yd r at e ( CH O ) i s th e m ai n
P . 5 0 -1 0
d e t e rm in an t of in su li n dem a nd an d i s c omm o nl y us e d t o d e te r m i ne t he pr e - m e al i n su li n d os e .
F u r t he r mo r e, p at ie n ts usi n g f i xe d d os es o f in su li n o r o ra l h yp og l yc em ic a ge n ts mu st ea t m e al s
c o nt a in in g c o ns is te n t a mo u n ts o f c a r bo h yd ra t e t o a vo i d h yp og l yce mi a . A vo i di n g “ su g a r” o r
s uc r os e d o es no t p r e vent “ su g a r d ia be t es . ” Si nc e i so ca l o ri c am o un ts o f suc r os e a n d s ta r ch
p r o du ce t he s am e d e g ree g l yc em i a, su c ro se c a n b e s u bs ti t u te d f o r a po r t io n of t he to t al C H O
i n t ak e a nd s h ou l d b e i nco r p o ra t ed in t o a n o th e r wi s e h ea l th f ul di e t.
Table 50-3 Estimating Ideal Body Weighta
1. Obtain height and weight.
2. Determine body frame (small, medium, or large).
3. Calculate ideal body weight:
o Female: 100 lb (45 kg) for first 5 ft plus 5 lb (2.3 kg) for every inch over 5 ft
o Male: 106 lb (48 kg) for first 5 ft plus 6 lb (2.7 kg) for each inch over 5 ft
Add 10% for large frame or subtract 10% for small frame
a
The term reasonable body weight also is used. Reasonable body weight is defined as a
weight that is achievable and maintainable for the patient, which may not be in the range
considered desirable. Any weight loss, even 10 to 20 lb may dramatically improve glycemic
control. Weight goals should always be individualized.
Adapted from reference 36.
Table 50-4 Determining Caloric Needs
1. Determine basal energy expenditure (BEE) using the Harris-Benedict equation299:
o Female: 655 + (9.6 × weight [kg]) + (1.9 × height [cm]) - (4.7 × age)
o Male: 66 + (13.7 × weight [kg]) + (5 × height [cm]) - (6.8 × age)
2. Select appropriate activity factor:
o Sedentary: multiply by 1.3
o Moderately active: multiply by 1.45
o Heavily active: multiply by 1.6
3. Caloric needs = BEE × activity factor
4. For weight gain, add 500 calories to gain 1 lb/week. To lose weight, subtract 500
calories.
W hole gr a in s, f r ui ts , a n d ve g e ta b le s h ig h i n f i be r a r e re co mm e nd ed f or p eo p le wi t h di a be t es a s
t h e y a re fo r t he ge ne r a l p o p ul at i on . Th e re is no e vi d e nc e t ha t l a r ge r am ou n ts p ro d uc e a
d i f fe r e nt ia l m e ta bo l ic b en e f it wi t h re g a rd to pl asm a g l uc os e a nd li p id l e ve l s. N on n u tr i ti ve
s w e e te ne r s ( sa cc h ar i n, a s pa r t am e, ac es ul f am e p o t ass i um , s uc r al os e ) ha ve b ee n ri go r o us l y
t e s te d b y t he F D A f o r s af e t y i n p eo pl e wi t h d ia b et e s a nd a re sa f e a t a pp ro ve d da il y i n ta ke s.
N u t r i ti ve s we e te n er s ( s or b i to l a n d f r uc t os e ) p ro du c e l o we r po st p r an di a l gl u co se r es po ns es
t h a n su c ro se , gl uc os e , an d s t a rc h . H o we ve r , pa t ie n ts sh o ul d b e a d vis ed th a t wh e n t h es e
s we e t e ne r s a r e us e d i n fo o ds la b el ed “ di e te t ic , ” th e y s ti ll p ro vi d e su bs t ant i a l ca l or i es .
F u r t he r mo r e, e xc e ss i ve in t ak e o f s o r bi t ol -s we e t en e d f o od s ( e .g . , 3 0 t o 5 0 g / da y) c an i n du ce an
o sm o ti c d ia r r he a , a n d e xc es si ve am o un ts o f f r uc to s e ca n i n cr e as e t o ta l an d lo w - d e n si t y
l i po p r ot e in (L D L ) c h ol es te r o l.
Counting Carbohydrates
W hen p at i en ts a re ta u ght t o e st im a te t he g ra ms of c ar b oh yd r a te in a me a l t h e y a re gi ve n th e
f o l lo wi n g g u id e li ne : O ne c a r bo h yd ra t e s e r vin g = 1 s t ar c h o r 1 f ru i t o r 1 m i lk = 1 5 g
c a r bo h yd ra t e . P a ti en t s va r y wi t h r e ga r d t o t h ei r in s ul in : C H O r a ti o t h r ou gho u t ti me an d
t h r o ug ho u t t h e d a y; h o we ve r , a t yp ic al st a r ti n g po i n t is 1 u ni t /1 5 g C H O . E xa m p l e s o f o ne
c a r bo h yd ra t e s e r vin g i ncl u de 1 s li ce b re ad , ¼ bag e l , ½ En gl is h m u ff i n o r h a mb u rg e r b u n, ¾ c
d r y c e re al , ½ c co o ke d ce r e al , ½ c le g um es , 1 / 3 c pa s ta o r r ic e , ¼ l a rg e b a ke d p o ta t o, 4 c
p o pc o rn , 1 sm al l f r u it , ½ f r u it ju ic e , 1 c m i lk , ½ c i c e c re am , 2 sm al l c oo kie s .
Fat
C a r d io va sc u la r d is e as e is a m aj o r c au se of m o r bid i t y an d m o rt a li t y in pa t ie n ts wi t h di ab e te s .
Th e r e f o re , a r ed u ce d f a t d i e t ( < 30 % o f t h e t o ta l ca l o ri es ) wi t h <1 0% o f ca lo r i es f ro m sa t u ra t ed
f a t s a nd <1 0 % f r om p o l yu n sa t u ra t ed fa t s is r ec om me n de d . Th e r ec om men d e d ch o le st e r ol
i n t ak e is < 30 0 m g/ d a y for p a ti e nt s wi t h di a be t es wh o h a ve no r ma l p l asm a c ho l es te r o l
c o nc en t r at i on s. F or pa t ien t s wi t h e le va t ed L DL cho l es t e ro l ( ≥ 1 00 mg / dL ) , < 7 % o f to t al c a lo r ie s
s h ou l d b e f r om s a tu r at e d f a t , a nd c h ol es t e ro l i n tak e s ho u ld be r es t ri ct e d to < 20 0 m g /d a y.
Th e s e g u id el i ne s a r e con s is te n t wi t h t ho se o f t he N a ti o na l Ch o le st e r ol Ed u ca t io n P ro g ra m. 1 3
Protein
D a t a a r e i ns u f fi ci en t to su p p or t s p ec ia l d ie t a r y pro t e in r ec omm e nd a ti on s fo r p er so n s wi t h
d i ab e te s i f k id n e y fu nc t io n is n o rm a l. G e ne r al l y, 1 5 % t o 2 0 % o f t h e d ai l y c a lo r ic i n t ak e co me s
f r o m a ni ma l a n d ve g et a bl e pr o t ei n s ou rc e s in t he U . S . d ie t . Th i s a mo un t ma y b e l i be r al i ze d i n
p r e gn a nt an d l ac t a ti ng wo m en o r i n e ld e rl y p eo p le . W it h t h e o ns et o f n eph r o pa t h y, a lo we r
p r o t ei n i nt a ke of 0. 8 g / kg p e r d a y i s c on si de r e d s u f fi ci en t l y re s t ri ct i ve .3 6
Sodium
Th e A D A h as no pa r ti cu la r r es t ri c ti on s o n s od i um i n ta ke , bu t re co mm en ds i n di vi du a li zi n g
a m ou n ts b a se d o n t h e pa t i en t ' s se n si ti vi t y t o s alt a nd co nc u r re n t c on di t ion s s uc h a s
h yp e r t en si on o r n ep h r opa t h y. In ge n e ra l, so d iu m i n t ak e sh o ul d b e l im i te d t o <2 , 4 00 m g /d a y ( o r
6 , 0 00 m g N a Cl ) .
Alcohol
Th e A D A ' s r ec om me nd a ti o n f o r a lc o ho l i s co ns is te n t wi t h g en e r al re c omme n d at io n s o f n o mo r e
t h a n t wo d r in ks pe r da y fo r me n o r on e d r in k /d a y f o r wo m en . A d r in k i s e qu i va le n t t o 1 2 o z
b e e r , 5 o z wi n e , or 1 o z d i st i ll ed sp i ri ts . N e ve rt he l es s, i ts c al o ri c c on t r ibu t i on m us t be
c o ns id e re d (1 al co h ol ic b e ve r ag e = 2 f a t e xc h a ng e s ), an d i t s h ou ld al wa ys be t ak en wi t h fo od
t o mi ni mi ze it s h yp o gl yce m ic e f f ec t. Th e ef f ec ts o f al co h ol on gl uc os e m et a b ol is m a r e
a d d re ss e d mo r e f u ll y l ate r in t hi s ch a pt e r .
Exercise
E xe r c i s e i s a k e y fa c to r in t he t re a tm en t of di a be te s , p a rt ic u la r l y in t ype 2 d i ab e te s , b ec au se
o b es i t y a n d i na ct i vi t y c on t r ib u t e t o t he de ve l op me n t o f gl uc os e i n to le r a nce i n g en e ti ca ll y
p r e di sp os e d i nd i vi du al s . R e g u la r e xe r c i se r ed uc es ch ol es t e ro l l e ve ls , l o we r s B P, au g m e nt s
we i g h t - r ed uc t io n d i et s , re d uc es t he do se re q ui r em e nt s o r ne ed f or in su l in o r o ra l a n ti di a be t ic
a g e nt s, en h an ce s i ns ul i n s en si t i vi t y, a nd im p ro ves ps yc ho l og ic al we l l - be ing b y r ed uc i ng s t r es s.
E xe r c i s e i nc r ea s es g l uc os e u t il i za ti o n, wh i ch is pro vi d e d i n i ti a ll y f r om th e b r e ak do wn o f m u sc le
g l yc og e n a nd , s ub se q uen t l y, f ro m
P . 5 0 -1 1
h e p at ic gl yc og e no l ysi s an d gl uc o ne og e ne si s . Th es e e f f ec ts ar e m e di at e d th r o ug h
n o r ep i ne p hr i ne , e p in e phr i n e, g ro wt h h o rm on e , c or t i so l , a nd gl uc a go n , a lon g wi t h th e
s u pp r es si o n o f i ns ul in sec r e ti o n. In in su l in - de p end e n t d ia b et ic pa t ie n ts , hyp e r g l yce mi a ,
n o r mo gl yc em ia , o r h yp og l yc em ia c a n o cc ur se con d a r y to e xe r c is e d ep e nd i ng on t he de g re e o f
c o nt r o l, r ec en t a dm i ni st ra t i on of in su l in , a n d f oo d i n ta ke . E xe r c is e i n p a ti en t s t ak i ng i n su li n
m us t be te mp e r ed b y i ncr e a se d f o od in t ak e, de l aye d a dm in is t r at i on of in su l in , de c re as ed do s es
o f in su l in , o r a co mb i na t io n of t he se ac ti o ns to m in i mi ze h ypo g l yc em i a ( see Q u es t io n 2 4 ) .
I n t he t ype 2 d ia b et ic pop u la t io n , p la sm a g lu c os e c on ce n t ra t io ns us ua l l y de c r ea se in r es po ns e
t o e xe r c is e ; s ymp t om at ic h yp o gl yc em ia is un co mm o n. B ec au se di a be t ic in d i vid u al s a r e
p r e di sp os e d t o c a rd io vas cu l a r d is ea se , a t t en t io n h as be e n f oc us e d o n t he me t ab o li c r es p on se
o f t he di ab e ti c p a ti en t to e xe r c i se . In ge n er a l, mod e r a te , re gu l a r e xe r c is e i s h i gh l y
r e c omm e nd e d f o r i nd i vidu a ls wi t h t ype 2 d ia b et es t r e at e d wi t h di e t a n d/ o r o r a l a ge n ts an d
e n co u ra g ed in in d i vid ua ls t ak in g i ns ul i n i f s pe ci al p r ec a ut i on s a r e t ak en .
Pharmacologic Treatment
I n su l in , a l on g wi t h d ie t , is cr u ci al to t he s u r vi va l o f in d i vid ua ls wi t h t ype 1 d i ab e te s a nd pl a ys a
m a jo r ro l e i n t he t he r ap y o f pe op l e wi t h t yp e 2 d ia b e te s wh e n t he i r s ymp to ms ca n no t b e
c o nt r o ll ed wi t h di e t o r o ra l an t id ia b et ic ag e nt s . I ns u li n a ls o i s us e d f o r p a ti e n ts wi t h t yp e 2
d i ab e te s d u ri n g p e ri od s o f in t e rc u rr e nt il l ne s s o r s t r es s ( e .g . , s ur g e r y, p r eg n a nc y) . Th e u se of
o r a l a n ti di a be t ic a g en ts is r es e r ved fo r t he t re a tme n t o f pa t ie n ts wi t h t yp e 2 d ia be t es wh o se
s ym p to ms c a nn o t b e co nt r o ll e d wi t h di e t a n d e xe r c is e a l on e . Th e cl in ic a l us e o f th es e a g en ts
a n d t h e co m pl ic at i on s a ss oc i at e d wi t h t he i r u se ar e di sc us se d l a te r in th is c ha p te r .
Pancreas and Islet Cell Transplants
P a n c re as t ra ns p la n ta ti o n i s t h e o nl y a va il ab l e t r ea t me n t f o r t yp e 1 di a be te s m el l it us t ha t
i n du c es a n i ns u li n -i n de pe n d en t , n o rm og l yce mi c st a t e . B ec a us e i t r e qu i re s i mm un os u pp r es si o n,
i t ha s b ee n m os t wi d el y u s ed in u re mi c d ia be t ic re c ip ie n ts of ki dn e y t r an sp l an t wi t h a hi g h
s uc c ess r at e , p a rt ic u la r ly wh e n p e r fo r me d s im ul ta n e ou sl y. As o f O c to b e r 2 0 0 2, 14 , 00 0
p a nc r ea s t r a ns pl an t a ti ons ha d b e en pe r f o rm ed in t h e Un i te d St a te s. Th e 1 - ye a r g r a f t su r vi va l
r a t es ( de f in ed as to t al f re e d om f r om in su l in th e rap y, n o rm al fa s ti ng bl o od g l uc os e
c o nc en t r at i on s, an d n o rm a l o r o nl y s li g ht l y el e vat e d A 1 C va lu e s) a re mo r e t h an 80 % . 3 8
P a n c re as t ra ns p la n ta ti o n i mp r o ves t he qu al i t y of li f e , b ut t he r e i s li t t le e vid e nc e t h at t he
d e ve l o p me n t o f mi c ro va sc u la r or ma c ro va sc ul a r co m pl ic a ti on s a r e p r e ven te d o r sl o we d .
F u r t he r mo r e, t he r e i s n o e vi d e nc e t ha t p a nc r ea s tr a n sp la n ta t io n p r o lo ng s li f e . Th e A D A
c o ns id e rs pa nc r ea t ic t ran s pl a nt a ti o n a via b le op ti o n f o r d ia b e ti c p at ie n ts wi t h e n d -s ta g e r e na l
d i se as e ( ES R D ) wh o mus t un de r g o ki d ne y t r an spl a n ta t io n . H o we ve r , pa n cr e a ti c t r a ns pl an t a ti on
a l on e i n a pa t ie n t wi t h d ia b e te s me l li t us re ma i ns c o nt r o ve rs i al be ca us e t he d is ad va n ta g es o f
e xo g e n o us in su li n th e rap y a r e re pl a ce d wi t h r is ks o f t he t ra ns p la n ta t io n p r o ce du r e i t se lf an d
t h e c om pl ic a ti o ns o f immu n os u pp r es si ve m e di ca t io n s. 3 9
I s le t c e ll t ra ns pl a nt s h a ve r ec e i ved in c re as ed a tte n t io n wi t h t he su cc es s o f t he “ Ed mo n to n
P r o t oc ol , ” wh i ch us ed a s t e ro i d - f r ee imm u no su p pr e ss i on re g im en as we l l a s o t he r te c hn iq u es .
A l l p a ti e nt s a ch i e ved in su l in in d ep e nd en ce a ft e r 1 ye a r i n c on t r as t t o a p re vi o us s u cc ess r at e
o f 8% . Ma n y i ss ue s r e ma i n r e ga r di n g i sl et ce ll t ra n sp l an t at i on , i nc l ud in g a va i la b il i t y o f
t r a ns p la n t ma t e ri al an d as se ss me n t o f l on g te r m o u tc om e s. 4 0 , 4 1
Overall Goals of Therapy
S p e ci f ic t h e ra p eu ti c e n dp o in t s va r y wi t h d if f e re n t vi e wp o i n ts on di ab e ti c co n t r ol an d t h e
m e th o ds u s ed to m o ni t o r d i ab e ti c t he r a p y (i . e. , b lo o d g lu c os e a nd A 1 C ). Th e se a re di sc us se d i n
a p p ro p r ia t e se c ti on s o f th i s ch a pt e r . H o we ve r , som e o ve r a ll go al s o f t h e rap y a r e a g r ee d o n b y
m os t di ab e to l og is ts :

Tr y t o k e ep pa t ie n ts fr e e o f s ym p to ms a ss oc ia t ed wi t h h yp e rg l yce mi a (p o lyu r i a ,
p o l ydi p si a, we i g h t l oss , fa t i gu e , r ec u r re n t i nf e ct i on , ke t oa ci do si s ) o r h yp og l yc em ia
( h u ng e r , a n xi e t y, pa l pi tat i o ns , s we a t in es s ).

S t r i ve fo r c o nt r o l a t l ea st e q ua l t o th a t ac h ie ve d in t he in t en si ve l y t re a t ed p a t ie n ts i n
t h e D C C T. Th i s ma y n o t b e ap p ro p r ia t e f o r a ll pa ti e n ts a n d mu s t b e b as ed o n s ou n d
c l in ic al ju d gm en t . Ta rg e t b l oo d g lu c os e g oa ls m ay n e e d t o b e a dj u st e d f or p a ti e nt s wi t h
f r e q ue n t, s e ve r e h yp og l yc em i a o r h yp o gl yc em ia un a wa r e n es s ( se e Q ue st io n s 3 5 a nd
3 9 ) . I n a d di t io n , es t ab l ish e d re na l i ns u f fi ci en c y, p r o li f e ra t i ve r e ti n op a th y, s e ve re
n e u ro p at h y, an d o t he r ad va n ce d c om pl ic a ti o ns ar e n ot li ke l y to be im p ro ve d b y ti gh t
g l uc os e c on t r ol .

Ma i n t a i n n o rm al g ro wt h a n d d e ve lo pm en t in c h il dr e n . Ad ol e sc en ts we r e inc l ud e d in t he
D C C T; h o we ve r , yo u n g er c hi l dr e n we r e n o t. In t ens i ve th e ra p y is no t re com me n de d f o r
c h il d re n you n ge r th a n 7 ye a r s o f ag e a nd sh o ul d b e us ed ca u ti ou sl y i n c hil d r en ag es 7
t o 13 ye a rs ol d ( se e Q ues t io ns 20 an d 2 1 ) .

E l i mi na t e o r m in im i ze a l l o t he r c a r di o vas cu l ar r isk f ac to r s ( o be si t y, h ype r te n si o n,
t o b acc o us e, h ype r li p id em i a; Ta b le 50 - 5 ) .

Tr y t o i n t eg r at e th e p a ti en t in t o t h e h ea l th c a re t ea m th r ou g h i nt e ns i ve e du c at i on . Th e
p a t ie n t 's k n o wl e dg e a n d u n d er s ta nd i ng of t hi s d ise a se c a n f a vo ra b l y i n fl ue n ce it s
o u tc om e s ( se e Ta bl e 5 0 -1 6 ) .
Table 50-5 American Diabetes Association Goals for Adults With Diabetes Mellitus44
Glycemic goals
• A1C
<7.0% (normal, 4–6%)a
• Preprandial plasma glucose
90–130 mg/dL (5.0–7.2 mmol/L)
[Blood glucose equivalent
80–120 mg/dL (4.4–6.7 mmol/L)]
• Postprandial plasma glucose
<180 mg/dL (<10.0 mmol/L)
[Blood glucose equivalent
<160 mg/dL (<8.9 mmol/L)]
Blood pressure
<130/80 mmHg
Lipids
• LDL
<100 mg/dL <2.6 mol/L)
• Triglycerides
<150 mg/dL (<1.7 mmol/L)
• HDL
Men
>40 mg/dL (>1.1 mmol/L)
Women
>50 mg/dL (>1.4 mmol/L)
Goals must be individualized to the patient. See Questions 2, 21, 46, 78, and 80 for broader
discussion.
a
More stringent goals (i.e., <6%) can be considered.
P . 5 0 -1 2
Methods of Monitoring Glycemic Control
I n ad d it i on to mo ni t o ri ng s ig ns an d s ym pt om s a ss oc i at e d wi t h h yp er g l ycem i a, h ypo g l yc e mi a,
a n d t h e l on g - te rm co mp lic a ti o ns o f di ab e te s , a n on g oi n g a ss ess me n t o f me t a bo li c c on t r ol is a n
i n t eg r al co mp on e nt o f d ia b e te s ma n ag em e nt . Id ea l l y, s el f -m o ni t o re d b lo od g lu co se ( S MB G )
r e s ul ts co mb in e d wi t h lab o r a to r y me as u re s o f a cu t e a n d ch r o ni c g l yc em i a c an be us e d t o
e va l u at e a n d a dj us t t h e ra p y. S e ve ra l c he mi ca l me a su r em e nt s ma y b e u sed b y t he pa t ie n t a nd
c l in ic ia n to ass es s g l ycem ic co n tr o l d i re ct l y o r i nd i r ec tl y. 4 2
Urine Ketone Testing
U r i n e k et o ne te s ti ng is re c omm e nd e d f o r p at i en ts wi t h ge st a ti o na l a n d t yp e 1 d ia b et es . U ri n e
k e to n es s h ou ld be e val ua t e d wh e n gl uc os e c o nce n t r at i on s co ns is t en t l y exc e e d 3 00 mg / dL
( 1 6 . 7 mm ol / L ) o r d u ri n g a c ut e i l ln es s. 4 2 P e rs is t en t l y hi g h g lu co se c o nc ent r a t io ns of t hi s
m a gn i tu d e si g na l i ns ul i n d e f ic ie nc y t ha t c a n, in t ur n , le a d t o l ip ol y s is an d k e to ac i do si s . A
p o si t i ve t es t m a y in di ca te im p en di n g o r e s ta bl is he d k e to a ci do si s a nd de ma n ds a mo r e
e xt e n s i ve di ag n os ti c wo rk u p. Te s ti n g a ls o is r ec om me n de d d u ri n g p r eg n an c y an d i f th e p a ti e nt
h a s s ymp t om s o f ke t oa cid o si s. A lt h ou g h t he r e a re g en e ra l l y n o k e to ne s in t he u ri n e, th e y ma y
b e p re se n t i n p eo pl e wh o a r e o n e xt r e m el y l o w ca l o ri c d ie t s a nd in th e f i rs t m o rn i ng sa mp le o f
wo m e n wh o a re p re g na n t. A ls o , s ee di sc us si on s of s ick da y m an ag em e n t an d k e to a ci do si s i n
o t h e r se c ti on s o f t h is c ha p t e r ( Q u es ti o ns 31 an d 4 0 th r o ug h 4 6 ).
Plasma Glucose
F P G c on ce n t ra t io ns ( no rm a l F P G , 3 . 9 t o 5 . 6 mm ol / d L o r 7 0 t o 1 0 0 mg / dL ) a r e c om mo n l y u se d
t o as se ss g l yc em ic c on t ro l in th e f a st in g s t at e b ec a us e t hi s i s wh e n gl uc os e c on c en t ra t io ns a re
m os t re p r od uc i bl e . F P G c o nc en t r at i on s g en e ra l l y r e f le ct gl uc os e de r i ved fr o m h e pa t ic g l uc os e
p r o du c ti on be c au se th is i s th e p r im a r y s ou r ce o f g l uc os e i n t h e p os t ab so rp t i ve s t at e . Th e F P G
i s th e m os t f r eq u en t te st p e r fo r me d b y p at i en ts at h om e wh e n se l f -m on i tor i n g. P os t p ra nd i al
g l uc os e c on ce n t ra t io ns (1 t o 2 ho u rs af t e r t he st ar t o f t h e me a l) al so a re u s e d t o a ss es s
g l yc em ic c o nt r ol wh e n fas t in g g l uc os e c on ce n tr a tio n s a r e wi t h i n n o rm al l im i ts or wh e n th e re is
a n ee d t o a ss es s t h e e ffe c ts of d ru gs on me al - r ela t e d g l yc em i a ( e .g . , l is p ro , α - g lu co si da s e
i n hi b it o rs ) . In no nd i ab e tic in d i vid ua ls , gl uc os e c on c en t r at i on s g en e ra l l y ret u r n t o <1 40 mg / dL
( 7 . 8 mm o l/ L ) wi t hi n 2 hou r s a f te r a m ea l . O n e t o 2 - h ou r po s tp r an d ia l c on ce n t r at i on s p ri ma r i l y
r e f le c t t he e ff ic i en c y o f in s ul in - me d ia t ed gl uc os e u p t ak e b y p er i ph e ra l ti ssu e .
B e c au se an y g lu co se con c en t r at i on c a n b e a f fe cte d b y va ri o us fa ct o rs ( e.g . , m e al s,
m e di ca t io ns , s t r ess ) , m ea s u re me n t a t a s i ng le poi n t i n t im e c an n o t b e us ed t o a ss ess a
p a t ie n t 's o ve ra ll co n tr o l. Mo s t l a bo r a to r ie s m ea sur e pl a sm a g lu co se c o nc en t r a ti o ns ra t he r th a n
wh o l e b lo od be ca u se th es e val u es ar e n o t s ub je ct t o c ha n ge s i n t he he mat o c ri t . W hol e b lo o d
g l uc os e c on ce n t ra t io ns ar e a pp r o xi m at e l y 10 % t o 1 5 % l o we r t ha n p la sm a g l uc os e
c o nc en t r at i on s b ec au se g l uc os e i s n ot di s t ri bu t ed i nt o h em o gl o bi n. To con ve r t pl as ma gl uc os e
c o nc en t r at i on s ( mg / dL ) to w h o l e b l oo d g lu co s e va l ue s (a nd vi ce ve rs a ) , th e fo l lo wi n g eq ua t io n
c a n b e u se d :

W hole bl oo d g l uc os e ( mg / d L ) = Pl as ma gl uc os e (m g /d L ) × 30 . 85

To c o n ve r t a g lu c os e con c en t r at i on in m g /d L t o m mo l /L , a f ac to r o f 1 8 is u se d :
P l a sm a g lu co se (m mo l /L) = P la sm a g lu co se (m g /d L ) ÷ 1 8
Self-Monitored Blood Glucose
Th e a d ve nt o f S MB G h a s m ad e e u gl yc em ia , bo t h p r e p ra n di al l y an d p os t p ra n di a ll y, an
a c hi e va bl e g oa l (8 0 t o 14 0 m g /d L ) . P a ti e nt s a nd t h e ir h ea lt h c a re p ro vi d er s a re no w a b l e t o
a ss e ss d i re c tl y t he e ff ect s of d ru g d os es , m e al s, e xe r c i s e, an d i l ln es s o n d a il y b lo o d g lu co se
c o nc en t r at i on s. W it h i mpr o ve d te ch n ol o g y a n d d ec r e as in g c os ts , S MB G i s t h e d a y - to - d a y
m o ni t o ri ng t es t o f c ho ic e f o r a l l p at i en ts wi t h di abe t es . H o we ve r , S MB G r e m a in s e xp e n si ve f or
s om e p a ti e nt s , is in va si ve , an d i s t ec h ni qu e d e pen d e nt . Fu r th e rm o r e, to ac h ie ve m a xi m u m
b e n ef i t f r om S MB G , b o t h t h e c li ni ci a n a nd th e p a ti e n t mu s t b e mo t i va te d an d wi l li n g t o s pe n d
t h e ti me re q ui r ed t o i nt e rp r e t t h e d at a a n d m od if y t h e ra p y to im p ro ve gl yce m ic c on t r ol . Ba se d
o n th e re su l ts of th e D CC T a n d U K P D S , m os t p er s o ns wi t h d ia b et es sh o ul d at t em p t t o ac h ie ve
a n d m ai n ta in bl o od gl uco s e l e vel s a s cl os e t o n or m a l as is s a fe l y po ss ib le . Th i s g oa l c an
r e a li st ic a ll y b e a ch ie ve d o n l y b y u si n g S MB G . Th e f r eq u en c y a n d t im in g of p e rf o rm i ng S MB G
s h ou l d b e d ic ta t ed b y the i nd i vid u al ' s n e ed s a nd g o al s . S e le ct i on an d u se o f S MB G t e s ti n g
m a te r i al s a re di sc us se d in Q u es t io ns 10 an d 1 1 . P a t i en ts in wh o m b lo o d g l uc os e s el f m o ni t o ri ng is pa r ti cu l a rl y va l u ab le in cl u de t he fo llo wi n g :

P a t i en ts w i th ty pe 1 d ia be t es : F re qu e nt bl o od gl uc os e m e as ur em e n ts h e lp t h e p a ti en t
c o r re l at e m ea ls , e xe r c ise , an d i ns u li n d os e wi t h b l oo d g l uc os e c on ce n t rat i o ns . Thi s
i n st a nt f ee db ac k g i ves the p at i en t a n i nc r e as ed se n se of co n t ro l a nd mo t iva t i o n,
l e ad i ng to im p ro ve d g l uco s e co n t ro l .

P r e g na n t p a ti en t s: In f an t m o rb i di t y an d m o rt a li t y a r e ass oc i at e d wi t h t he m o th e r ' s
o ve r a ll gl uc os e c o nt r ol . U s i ng S MB G , t h e m o th e r wi t h d ia b et es wh o ac h ieve s
n o r mo gl yc em ia be f o re co n ce p ti o n a nd th r ou g ho ut p r eg n an c y, i mp r o ves he r ch a nc es o f
d e li ve r i ng a l i ve, he a lt h y i n fa n t.

P a t i en ts ha vi n g d if f ic ul t y r e co g ni zi n g hy p og ly ce mi a : O ve r t im e , m an y p at ie n ts wi t h
d i ab e te s d e ve lo p a s l ug gi s h co u nt e r - re g ul a to r y r es p on se t o h yp og l yce mi a wh e r e b y
h yp o g l yc em ic s ym p to ms a r e bl un t ed o r e ve n a bs en t . Th is is o f t en re f e r re d t o as
h y po g lyc e mic un a w a re n es s . R o ut i ne S MB G t o d e te c t a s ym p to ma t ic h ypo g lyc e mi a i s
e ss e nt i al in th es e i n di vi du a ls (s e e Q u es t io n 3 9 ) . In a dd i ti on , ac ut e a n xi e t y a t t ack s o r
s i gn s a nd s ym p to ms asso c ia t ed wi t h a r ap i dl y f all i ng bl o od gl uc os e c on cen t r a ti o n ma y
m im ic a t r ue h yp og l yce mi c re ac t io n . Th i s c an be e va l u at e d e as il y b y me as u r in g a
f i n ge r st ic k b lo o d g lu co se c on ce n t ra t io n .

P a t i en ts w ho a re us in g in t e ns iv e i ns ul i n t he r ap y : I n di vi d ua ls wh o a re on m u lt i pl e d ai l y
d o se s o f i ns ul i n o r t h os e u si n g a n i ns ul in p um p sh o ul d u s e S MB G t o e va lu a t e t he
e f f ec t i ven es s o f t h ei r i nsu l in r eg im e ns a n d me a l p l an s a n d t o ch e ck f o r hyp o g l yce mi c o r
h yp e r gl yc em ic r ea ct i on s ( s e e Q u es t io n 1 1 ) . K n o wl e dg e o f p re p ra n di al , pos t p ra n di al ,
b e d ti me , a n d n oc tu r n al (e . g . , 2 A M) b l oo d g lu co se co nc e n tr a ti o ns i s e ss en t i al in
d e t e rm in in g b as a l a nd p re p r an d ia l i ns ul i n r e qu i rem e nt s .
Glycosylated Hemoglobin
B e f o re t he m e as u re me n t o f gl yc os yl at e d h em og l ob i n , o r A 1 C , wa s a va i la ble , cl in ic i an s co u ld
i n f er o ve ra l l g l yc em ic con t r ol
P . 5 0 -1 3
o n l y b y e xt r a p o l at i ng in fo r m at i on f ro m a s e ri es of f as t in g o r ra n do m b lo od g lu co se
m e as u re me n ts . 4 2 Th e i nt r o d uc ti o n o f t he A 1 C t e st h as ma de p oss i bl e a n a c cu r a te as se ssm e nt
o f gl yc em ic c o nt r o l o ve r a d ef i ni t e t im e p e ri od . A 1 C i s m os t c omm o nl y me as u r ed be ca us e i t
c om p r is es th e m aj o ri t y of g l yco s yla t ed he mo g lo bin a nd is th e l ea s t a ff e ct ed b y r ec en t
f l uc t ua t io ns in bl o od gl uc os e . A 1 C m e as u re s t h e p e r ce n ta ge o f h em og l ob in A th a t h as be e n
i r r e ve rs i bl y g l yc os yl a te d a t t he N - te r mi na l a mi n o g r o up o f t he β -c h ai n ; t he p l asm a g l uc os e
l e ve l a nd t he li f e sp a n o f a r ed bl o od c e ll ( R B C ) (a p p ro xi m a t el y 1 20 d a ys ) d e te r mi n e i ts val u e.
Th u s , A 1 C is an in d ic at o r o f gl yc em ic c on t r ol o ve r t h e p r ec ed i ng 2 t o 3 m on t hs . In pa t ie n ts
wi t h o u t d i ab e te s, A 1 C c om p r is es a p p ro xi m a t el y 4% t o 6 % o f t h e t o ta l h emo g lo b in . Va l ue s ma y
b e th r e e t im es th is le ve l i n pa t ie n ts wi t h d ia b et es.
E a c h l ab o ra t o r y e s ta bl ish e s i ts o wn no r ma l val ues f or A 1 C b ec a us e d if f e ren t co mp on e n ts o f
h e mo g lo bi n A a r e me as ur e d b y d i ff e r en t a ss a y me t h od s. B ec au s e a 1 % ch a n ge i n th e
g l yc os yl at e d h em og l ob in r e p re se n ts a 3 5 -m g/ d L c h an g e i n t he m e an pl asm a g l uc os e
c o nc en t r at i on , i t i s i mp o rt a n t t o f o ll o w r e la t i ve c ha n g es i n A 1 C va lu es me as u r ed b y a si ng l e
l a bo r a to r y. A m o vem e nt t o st a nd a rd i ze m e th od s to t he D C C T va l u es is u nd e r wa y.
Th e c o r re la t io n b e t we e n t h e A 1 C le ve l a n d m ea n pl a sm a g lu co se le ve ls a re a s f o ll o ws 4 3 , 4 4:
Mean plasma glucose
A1C (%)(mg/dL) mmol/l
6
135
7.5
7
170
9.5
8
205
11.5
9
240
13.5
10
275
15.5
11
310
17.5
12
345
19.5
A l t e ra t io ns in R B C s u r viva l su ch as he mo g lo bi n op a t hi es , a n em ia s, ac u te o r ch r on ic bl o od lo ss ,
a n d u r em ia ma y a f fe ct A 1 C va l ue s , r es ul t in g i n i na cc u r at e i n di ca t io ns of gl yc em ic co n t ro l .
A n t i o xi d an t s su ch as vi tam i ns C a n d E al so m a y in t e r fe r e wi t h t he gl yc os yl a t io n p r oc es s 4 5 , 4 6
( s e e Ta b l e 5 0 - 6 ) .
A 1 C c an be m e as u re d wi th o u t a n y s p ec ia l p a ti en t p r e pa r a ti o n ( e .g . , f as t in g) a n d g en e ra l l y i s
n o t s ub j ec t t o a cu t e c han g es in in su li n d o si ng , exe r c i s e , o r d i et . N o rm al iza t i o n ca n i n di ca t e
wh e t h e r eu gl yc em i a h as b e e n ac h ie ve d . H o we ve r , A 1 C do es no t re p la ce the d a y - to - d a y
m o ni t o ri ng o f bl o od gl uco s e co n ce n tr a ti o ns , wh ich is es se n ti al f or e val u a ti n g a cu t e ch a ng es in
b l oo d g l uc os e c on ce n t rat i o ns . Th es e va l ue s a r e n e e de d t o a d ju st th e m ea l pl an o r m ed ic a ti on
d o se s.
Clinical Use
C u r r e n tl y, th e A 1 C va l ue i s u se d a s a n a dj u nc t t o a ss e ss in g o ve r al l g l ycem ic co n tr o l i n p at i en ts
wi t h d i ab e te s. O f t en , i t is us ed t o ve r i f y c li n ic al im p r ess i on s r e la t ed to glu c os e c on t ro l a n d
p a t ie n t a dh e re nc e . So me a ls o h a ve s u gg es t ed the us e o f A 1 C va l ue s f o r di a be t es s c re e ni n g
a n d d ia g no si s ; h o we ve r , u n t il th e t e st is s t an da r d ize d a nd m o r e s tu di es a re co mp l et e d, i t
c a nn o t b e r ec om me n de d f o r th es e p u rp os e s. A 1 C s h ou l d b e me as u r ed qu ar t e r l y in pa t ie n ts wh o
d o no t m ee t t re a tm en t go a ls , a n d a t l ea s t se mi an n u al l y i n s t ab le p at ie n ts wh o a re me e ti ng
t r e a tm en t g o al s.
Table 50-6 Factors Affecting A1C
Cause
Effect on A1C
Alterations in RBC Survival
Hemoglobinopathies
Decreased
Anemias
Hemolytic
Decreased
Iron deficiency
Decreaseda
Blood loss
Decreased
Assay Interference
Uremia
Increased or no changeb,c
Hemodialysis
No changeb
Antioxidants
Decreasedd
a
For patients receiving iron replacement therapy. Normal levels would be expected in
untreated patients.
b
Interference seen in assays using high-pressure liquid chromatography (HPLC) and
electroendosmosis. Affinity chromatography appears unaffected.
c
Carbamylated hemoglobin equaling 0.063% of total hemoglobin is formed for every 1
mmol/L of serum urea.
d
Reported with vitamins C (1 g/day) and E (1,200 mg/day). Possible mechanism is
competitive inhibition of hemoglobin glycosylation.
A1C, glycosylated hemoglobin; RBC, red blood cell.
Glycated Serum Protein, Glycated Serum Albumin,
Fructosamine
A s sa ys fo r gl yc at e d s er um p ro t ei ns ( G S P s) r ef l ect t h e e xt e n t of gl yc os yl a ti o n o f a va r ie t y o f
s e r um p r o te in s , i nc lu di ng g l yc a te d s e ru m a lb um in ( G S A ) . 42 Th e f ru ct os am i ne ass a y is on e o f
t h e m os t wi d el y us e d m et h o ds to m e as u re gl yc ate d p ro t ei ns (n o rm a l, 2 t o 2 . 8 mm o l/ L ) .
B e c au se th e h a lf - li f e o f a l bu mi n i s a pp r o xi m a te l y 1 4 to 20 da ys , f r uc t os am i ne p ro vi de s a n
i n di ca t io n o f gl yc em ic c on t r ol o ve r a s h o rt e r t im e f r a me ( 1 t o 2 we e ks ) t h an d oe s t he A 1 C . Th e
A D A d o es n o t c on si d er m e as u re me n t o f f r uc t os am i ne eq ui va l en t to th a t of A 1 C , e ve n th ou g h i t
c o r re l at es we l l wi t h t h is va l u e . F r uc to s am in e l e ve l s ma y b e u se f ul as a n a d ju n ct to A 1 C i n
d e t e rm in in g wh e th e r a pa t i en t i s im p r o vin g o r wo r s e ni ng in t he s h or t te r m ( e . g. , a p at i en t o n
i n su li n th e ra p y un d e rg oin g m u lt i pl e d os a ge ad ju st m en t s; fo r wo m e n wi t h typ e 2 d i ab e te s d u ri ng
p r e gn a nc y o r g es t at i on al d i ab e te s ) o r i n p a ti en t s wi t h c on d it i on s s uc h as h e mo l yt ic a n em ia in
wh o m t h e A 1 C t e st is i n ac cu r a te ( Ta b le 50 - 6 ). H owe ve r , t h e e xa c t r o le of G S P i n m o ni t or i ng
g l yc em ic c o nt r ol r eq u ir es f ur t he r st u d y.
Glycemic Goals
Th e A D A r ec om me n da t ion s fo r g l yc em ic g o al s a re su mm a ri ze d i n Ta bl e 50 - 5 . 44
Insulin
I n su l in is a ho r mo n e se cr e t e d f r om t h e p an c re a tic β - ce ll in r es po ns e t o g lu c os e a nd o th e r
s t im ul a nt s ( e .g . , a mi n o ac i ds , f r ee f at t y ac i ds , g as t r ic h o rm o ne s, pa r as ymp a t he t ic s t im ul a ti on ,
β - a d r en e r gi c st im u la t io n) . 4 7 , 4 8 Th e h o rm on e i s m a de up of t wo p ol yp e pti d e c ha in s (a 21 –
a m in o a ci d α c ha i n a nd a 3 0 – am i no ac id β c ha i n) , wh i c h a r e co n ne c te d by t wo d i s ul f id e b on d s
( F i g . 5 0 -3 ) . P r o in su li n , th e p re cu r so r o f in su li n , is a s in gl e -c h ai n , 8 6 – am in o ac id po l yp ep t id e .
I n t he s t o ra g e g ra n ul e o f t h e β - c el l, t he c o nn ec t ing o r C -p e pt i de i s c le a ved f r om p r o in su li n to
p r o du ce eq u im ol a r a mo un t s o f i ns u li n a nd C - pe p ti d e . Th u s , me as u r ab le C - p e p ti de le ve ls
i n di ca t e t h e p r es en ce of e n d og en o us l y p r o du ce d in s ul in an d fu nc t io n in g β -c e ll s. I ns ul in is
c r uc i al to
P . 5 0 -1 4
t h e s u r vi val of in d i vid u als wi t h t ype 1 d ia b et es wh o se β -c e ll s h a ve b ee n d e st r o ye d. I t a ls o
p l a ys a m aj o r ro le in t he t h e r ap y o f i nd i vi du al s wi th t yp e 2 di ab e te s wh e n th e i r s ymp t om s
c a nn o t b e c on t ro l le d wi th d ie t a l on e o r or a l a nt i di a be t ic ag e nt s. I ns ul in als o i s u se d i n p a ti en t s
wi t h t yp e 2 d ia be t es du r in g p re gn a nc y o r p e ri o ds o f in t e rc u rr e nt il l ne ss o r s t r es s ( e .g . ,
s u r ge r y) .
FIGURE 50-3 Proinsulin. Insulin is secreted from the
pancreas as proinsulin. The connecting or C-peptide is
cleaved to release the active insulin molecule. Thus, Cpeptide levels are measured in study conditions to confirm
the presence of a working pancreas. Insulin is a 51–amino
acid protein made up of an A chain and a B chain connected
by two disulfide bonds. (Reproduced with permission from
reference 298.)
View Figure
C o m me rc i al l y a vai la b le in s ul in p ro d uc ts di f fe r in t h e ir im mu n og en ic i t y, p hys i ca l a n d c he mi ca l
p r o pe r t ie s, ph a rm ac o ki ne t ic s , a nd ph a rm ac od yn am ic s .
Immunogenicity
Mo d e r n m an u fa ct u r in g p ro c es se s h a ve vi r t ua ll y e li m in a te d c on t am in a nt s f ro m c u r re n t p r od uc ts ,
a n d m os t p e op le no w u se h um an in su li n . Co ns e qu e n tl y, im mu no l og ic al l y m e di a te d s eq u el ae ,
s uc h a s l ip o d yst r op h y, hyp e r s en si t i vit y, a nd in su li n re si s ta nc e c au se d b y “ b l oc ki ng ” an t ib o di es ,
a r e ra r e . W hen th es e e ve n ts do oc cu r , m os t a r e a ss o ci at e d wi t h b ee f o r p o r k i ns ul in s . B e ef ( or
m i xe d b ee f a n d p o rk i nsu l in ) p ro du c ts a r e m o re im mu n og e ni c t ha n p o rk in s ul in . P ur e b e ef
p r o du c ts a r e n o l o ng e r m a nu f ac tu r e d i n t he U ni te d S ta t es , a n d t he p ro d uc t io n o f m i xe d b ee f –
p o r k p ro d uc ts wa s di sc on t i nu ed in 19 9 8 . P u ri f ie d p o rk in su l in i s s li g ht l y mo r e i mm u no ge n ic
t h a n co mm e rc ia l l y a va i lab l e h um a n in s ul in ; h o we ve r , t he di f f er e nc e b e t wee n th es e i ns u li ns i s
s u bt l e. I n mo s t n e wl y d iag n os e d d ia be t ic pa t ie n ts, h um an in su l in c o ns is ten t l y p ro d uc es l es s
a n t ib od y r e sp o ns e t ha n p u r if i ed po r k i ns ul in , al be i t t h e d if f e re nc e o f t en is sl ig h t a nd p ro b ab l y
c l in ic al l y un im p o rt a nt . 49
Physical and Chemical Properties
R e g u la r i ns u li n i s a s ol u ti o n t h at ca n b e a dm in is te r e d b y a n y p a r en t er a l ro u t e: in t r a ven o us l y,
i n t ra m usc u la r l y, a n d su bc u ta n eo us l y. In su li n l is p ro a nd in su li n a s pa r t , r ap id - a ct i ng an al o gs ,
a r e al so c l ea r s ol u ti o ns a p p ro ve d b y t h e U . S . F oo d an d D ru g Ad mi ni s t ra tio n ( F D A ) f o r S C us e .
I n su l in gl a rg i ne , a lo n g - ac t in g i ns u li n i s a c le a r so l u ti on , bu t s ho u ld no t be a dm in is t e re d
i n t ra ve n ou sl y b ec a us e t he p r od uc t i s d es ig n ed to p r e ci pi t a te at ph ys io l og ic p H . A l l o th e r
i n su li ns ( N P H , L e nt e , Ul tr a l en t e ) a r e su sp e ns io ns i n wh ic h re g ul a r i ns ul i n h a s b ee n c om pl e xe d
o r c r ys t al l i zed to e xt e n d t h e ir ac t io ns wi t h pr o ta mi n e ( e . g. , N P H ) a nd wi t h va r yi n g am ou n ts o f
zi n c (e . g. ,
P . 5 0 -1 5
L e n te an d Ul t r al en t e ) . 4 7 Th e s e i ns ul i ns m us t b e m i xe d we l l be f o re ad mi nis t r at i on an d s ho u ld
n e ve r be ad mi ni s te r ed int r a ve n ou sl y. A ll in su li n pr o d uc ts ha ve a n eu t r al pH , e xc e p t fo r i n su li n
g l a rg i ne , wh ic h h a s a p H o f 4. 0 .
Pharmacokinetics: Absorption, Distribution, and Elimination
A f t e r S C i nj ec t io n , i ns ul in is ab so r b ed di r ec tl y i n to t he bl o od st r e am , b yp as si n g t he l ymp h at ic
s ys t em . Th e r a te - li mi t in g s t ep of in su l in ac ti vi t y af t e r S C a dm in is t r at i on is a b so r p ti on o f i ns ul in
f r o m t he in j ec ti o n si t e , wh i ch de p en ds on th e t ype o f i ns ul i n a dm in is t er e d, a s we l l as a
m u lt i tu d e o f o t he r fa ct o rs . Al t ho u gh S C ab so r p ti on g en e ra l l y fo ll o ws a s imp l e e xp o n e n ti al
c o u rs e, it is hi gh l y i r re gul a r . Co e ff ic i en ts o f va r i ati o n f o r t h e t im e u n ti l 5 0% o f t h e in s ul in do se
i s a bs o r be d a r e a pp r o xi m a te l y 25 % wi t hi n a n i n di vi d ua l a n d u p t o 5 0% am o ng pa t ie n ts fo r al l
i n su li ns st u di e d. 5 0 A p rim a r y ca us e o f t h is va ri a ti o n i s a tt r i bu t ed to ch an ge s i n b l oo d f l o w
a r o un d th e i nj ec t io n s i te .
E xo g e n o u s i ns ul in is de gr a d ed a t b ot h re n al a n d e xt r a r e n a l ( l i ver an d m usc l e ) si t es .
D e g r a da ti o n a ls o t ak es pl a ce at t he c e ll ul a r l e vel a f t e r i nt e r na li za t io n o f the i ns ul in - r ec e pt o r
c om p le x. A p p r o xi m a te l y 3 0 % t o 8 0 % o f i ns ul i n is c l ea r ed f ro m t h e s yst em ic ci rc u la t io n b y t h e
k i dn e ys, wh i c h h a ve a l ar g e r ro l e i n cl e ar i ng e xo g e n ou sl y a dm in is t er e d i ns u li n . E n do ge n ou s
i n su li n i s s ec r et e d d ir ec tl y i n to th e po r ta l c i rc ul a ti o n a nd is p ri ma r il y cl e a re d b y th e l i ve r i n
n o n di ab e ti c i nd i vi du al s (6 0 % ) . 4 7 I ns u li n i s f il t er ed b y gl om e r ul a r c ap il l ar ie s , b u t > 99 % i s
r e a bs o rb e d b y t he pr o xi m a l t ub u le s. Th e i n su li n i s th en de g r ad ed in gl ome r u la r c a pi ll a r y ce ll s
a n d p os t gl om e ru l a r p e ri tu b ul a r c el ls . 51 I ns ul in ph a r ma co ki n et ic s a r e su mm a r i zed in Ta bl e 50 7 . ( A ls o se e Q ue s ti on 32 . )
Pharmacodynamics
C l i ni c al l y, t h e mo s t im p or t a n t d if f e re nc es be t we e n i ns u l in p ro d uc ts re l at e t o t he i r o ns et an d
d u r a ti on o f ac t i vit i es . Cur r e n t i ns ul i n p r od uc ts can b e ca t eg o r i zed as ra p id o r u l t ra -s h o rt a c ti n g, sh o rt - ac t in g , i n ter m e di a te - ac ti n g, an d l o ng - a ct i ng . P ro du c ts a va i lab l e i n t h e U n it e d
S t a t es ar e l is t ed in Ta b le 5 0 -8 , a n d t he on se t of a c ti o n, pe ak e ff ec t , a n d d u r a ti on s o f a c ti on o f
e a ch in su li n c a te g or y a re i n l is te d Ta bl e 5 0 -9 . Ho we ve r , t h es e d a ta a re de r i ve d p r im a ri l y f ro m
s t ud i es i n n o rm a l, he a lt hy vo l u n te e rs in t he fa st i ng s ta t e o r i n we ll - co n t ro lle d pa t ie n ts wi t h
d i ab e te s s ta b il i ze d i n a m e ta b ol ic wa r d . In ac tu al i t y, i n te r su b je ct an d i n t ra s ub j ec t va r i at i on s i n
r e s po ns e t o i ns u li n a r e su b st a nt i al be ca us e a n i nd i vi du a l p at t e rn o f r es pon s e t o i ns ul i n ca n b e
a f f ec t ed b y n um e r ou s f ac t o rs (e . g ., th e fo r ma ti o n o f i n su li n h e xa m e rs , th e p r es e nc e o f i ns ul i n b i nd i ng an t ib o di es , d os e, e xe r c i se , s it e o f in je c tio n , m as sa g e o f t he in j ect i o n si t e, am bi e n t
t e mp e r at u re , an d i n te r act i o ns b e t we e n i ns ul i ns tha t ha ve be e n mi xe d t o g et h e r ) . 5 2 , 5 0 (S e e
Ta b l e 50 - 12 an d Q ue st i on 1 4 . ) N e ve rt h el es s , kn owl e d g e of wh e n o n e mi gh t e xp e c t t he va r i o us
i n su li ns t o e xe r t t he i r e f fe c ts is a bs o lu t el y es s en ti a l t o t h e r a ti o na l a dj us tm e nt o f i ns ul in
d o sa g es .
Rapid-Acting Insulin (Ultra -Short-Acting Insulin)
Insulin Lispro
I n su l in li sp r o [ L ys ( B2 8 ), P r o ( B 2 9) ] - hu ma n i ns u li n ( H u m al og , E li L i ll y) wa s t h e fi rs t a vai la b le
r a p id - ac t in g i ns u li n a na lo g an d re ce i ve d F D A a pp r o va l i n 1 99 6 . Th e n at ur a l a mi n o a ci d
s e qu e nc e o f t h e i ns ul in β - c h ai n a t p os i ti o ns 2 8 (p r o li n e) an d 29 (l ys in e ) is in ve r t ed to f o rm
l i sp r o. Th i s ch a ng e re su lt s in an i n su li n m ol ec u le t h a t m or e l o os el y s el f -a ss oc i at es in t o
h e xa m e r s t ha n d o es re gu l a r i ns ul i n. C on se q ue n tly, t h e a c ti ve m o no me r ic f o r m is mo r e r e ad il y
a va i la b le , re su l ti n g i n a n o ns e t o f a c ti vi t y ( 15 m i nu t es ) , p e ak ac ti o n ( 30 t o 9 0 m in u te s ), an d
d u r a ti on ( 3 t o 4 ho u rs ) th a t m o re cl os el y s i m ul a te s p h ysi o lo g ic i ns u li n s ec r e ti o n r el a ti ve t o
m e al s. B ec au se i t ca n be i nj ec t ed s h o rt l y be f o re e a t in g (0 to 15 m i nu t es ) , l is p ro p ro vi d es
p a t ie n ts g r e at e r f l e xi b il i ty i n li f es t yl e, lo we r s 2 -ho u r po st p r an di a l b lo od glu c os e l e vel s , a nd
d e c re as es r isk f or la t e po s tp r a nd ia l a n d n oc tu r n al h yp og l yce mi a c om pa r ed wi t h r eg u la r i ns u li n
f o r mu l at io n s. 5 3 P a ti en t s wh o u s e a n i ns ul i n p um p m os t o f te n us e a ra pi d -a c ti n g i ns ul in in s te a d
o f r eg u la r i ns u li n . O n e ra n d om i zed , t wo - wa y c r o s so ve r op e n -l ab e l s tu d y c om p a re d l is p ro wi t h
r e g ul a r i ns ul i n a dm in is t er e d fo r 3 mo n th s b y co n ti n u o us S C i ns ul i n i nf us i on . 5 4 L is p ro re s ul te d
i n A 1 C va l ue s t h at we r e si g ni f ic an t l y lo we r t h an tho s e p r od uc e d b y r eg ul a r i n su li n (7 . 41 %
ve r s us 7 .6 5% ) . Th e re we r e n o d if f e re nc es in ad ver s e e ve n ts . Be ca us e l is pr o h as a sh o rt e r
d u r a ti on o f ac t io n t h an re g ul a r i ns u li n , h yp e rg l yce m ia an d k et o si s ma y o cc u r m o re r ap id l y if
i n su li n d e li ve r y is in a d ver t e n tl y i nt e r ru p te d .
Table 50-7 Insulin Pharmacokinetics
Clearance
Total clearance
700–800 mL/min
Hepatic clearance
300–400 mL/min
Renal clearance
190–270 mL/min
IV Infusion
Elimination follows multicompartment model
Half-life for three compartments: 2.3–2.4 min, 14 min, 133 min
Insulin action most closely corresponds to last compartment. Therefore, it is unnecessary to
adjust the dose more frequently than Q 2 hr
SC Administration of Regular Insulina
Intermittent Boluses
Half-life (absorption, 70–120 min)
Half-life (elimination, 53 min)
SC Infusion
Steady state achieved in 68 hr
If infusion is discontinued, check for rise in glucose ketones after 2 or 3 hr. Because there
is no SC pool, effects dissipate quickly
C Administration of Intermediate-Acting Insulinsa
NPH half-life (absorption) 12–19 hr
a
Insulin absorption varies by 25% within the same individual and 50% among individuals.
See Table 50-12 for factors that influence absorption.
IV, intravenous; NPH, isophane insulin suspension; SC, subcutaneous.
Adapted from reference 50.
Insulin Aspart
I n su l in as pa r t ( No vo L og , N o vo N o r di sk ) , a ra pi d -a c ti n g i ns ul in an a lo g d e ve l op e d b y N o vo
N o r d is k, di f f er s f r om hum a n i ns ul in b y s u bs ti t u tio n of as pa r t ic ac id at B 28 . I ns ul in as pa r t
c o nt r o ls p os t p ra n di al gl uc os e e xc u r s io n s si mi la r to i ns ul in li sp r o . I ns ul i n as p a rt wa s ap p ro ve d
b y t h e F D A on Ju ne 7 , 20 0 0 .
Table 50-8 Insulins Available in the United States
Animal
Source/Manufacturing
Process
Brand Name
Insulin lispro
Recombinant DNA
Humalog
Lilly
Insulin aspart
Recombinant DNA
NovoLog
Novo
Nordisk
Purified
Pork
Regular
Iletin II
Lilly
Human
Recombinant DNA
Humulin R
Lilly
Novolin Ra
Novo
Nordisk
Velosulin
BRb
Novo
Nordisk
Type/Duration of Action
Manufacturer
Rapid-Acting
Short-Acting
Regular
Intermediate-Acting
NPH (Isophane Insulin Suspension)
Purified
Pork
Pork NPH
Iletin II
Lilly
Human
Recombinant DNA
Humulin N
Lilly
Novolin Na
Novo
Nordisk
Lente (Insulin Zinc Suspension)
Purified
Pork
Lente Iletin
II (Pork)
Lilly
Human
Recombinant DNA
Humulin L
Lilly
Novolin La
Novo
Nordisk
NPH/Regular Mixture
(70%/30%)
Recombinant DNA
Humulin
70/30a
Lilly
Human insulin analog
Recombinant DNA
Novolin
70/30a
Novo
Nordisk
Novolog Mix
70/30
Novo
Nordisk
Lilly
Humulin
50/50
Lilly
Humalog
Mix75/25a
Lilly
Insulin Aspart
Protamine/Insulin Aspart
Mixture (70%/30%)
Insulin Aspart
Recombinant DNA
NPH/Regular Mixture
(50%/50%)
Human insulin analog
Recombinant DNA
Insulin NPL/Insulin Lispro
Mixture (75%/25%)
Recombinant DNA
Long-Acting
Ultralente (Insulin Zn Suspension, Extended)
Human
Recombinant DNA
Humulin U
Lilly
Recombinant DNA
Lantus
Aventis
Insulin glargine
Insulin analog
These products also are available in 1.5 and 3-mL cartridges for use in “pen” delivery
devices (Novolin Pen and as prefilled pens).
b
Phosphate buffered product. Used in insulin pumps.
a
P . 5 0 -1 6
Short-Acting Insulins
R e g u la r i ns u li n h as an on s et o f ac t io n o f 30 to 60 mi n ut es , a p ea k e f fe ct a t 1 t o 5 ho u rs , a n d a
d u r a ti on o f ac t io n o f 5 t o 1 0 h o u rs . Th e b ro a d r a ng e in pe ak ef f ec t a n d d ur a t io n re f le c ts t h e
m a n y va ri a bl es th a t a f fec t in su li n a c ti on (s e e Ta b l e 5 0 -9 ) . Th e 3 0 - t o 6 0 -m i nu t e o ns et o f ac t io n
r e q ui r es p ro pe r ti mi n g o f p r em e al re g ul a r i ns ul i n, wh i c h i s d i ff ic u lt fo r m os t pa t ie n ts .
Intermediate-Acting Insulins NPH, Lente, and NPL
N P H ( n e ut r a l p ro t am in e h a g ed o rn o r is o ph a ne ) an d Le n te in su li n s a re in te r m ed ia t e -a ct i ng
i n su li ns . B ot h h a ve o ns et s of ac ti o n a t a p pr o x i m at e l y 2 h ou r s ( 1 to 3 h ou rs ) , p e ak ef f ec ts at
a p p ro xi m a t el y 6 to 14 hou r s , a nd du r a ti on s o f a c ti o n o f a p p ro xi m a t el y 1 6 to 2 4 h ou r s. A ga i n, it
m us t be em ph as i ze d t ha t t h is pa t te r n o f re sp o ns e i s a t b es t a g en e ra li za t io n . Pa t ie n ts
P . 5 0 -1 7
m a y ha ve a va ri ab l e p at te r n of r es po ns e t o b o th N P H a n d L en t e i ns ul i ns o ve r t im e, an d th os e
o n hi gh e r d os e s a re li ke ly t o h a ve a l a te r pe ak and a l o ng e r d u ra t io n o f a ct i o n t ha n th os e wh o
u s e l o we r do se s a n a ni ma l - so u rc e p r od uc t (e . g ., p u r if i ed po r k ve r su s h uma n in su li n ) . U p to
8 0 % o f th es e d a y - t o- d a y f l uc t ua ti o ns in bl oo d g l uc os e re sp o ns es c a n b e ac co u nt e d f o r b y
va r i a ti o n i n t h e a bs or p ti on o f t h e i nt e rm ed i at e - ac ti n g i ns ul i ns . 5 0 N P L is a p r o t am in e -b as e d
i n su li n l is p r o f o rm ul a ti on i n wh ic h i ns u li n l is p ro ha s b e en co -c r ys t al li ze d wi t h p r o ta mi n e t o
p r o du ce an in t e rm ed i at e - a c ti n g i ns ul in si mi la r to N P H . 5 5 It is a vai la b le as H u m al og Mi x 7 5 / 2 5 ,
a p r em i xe d in su li n fo rm ul a t io n c on t ai ni n g N P L a nd i ns ul in li sp r o i n a r at i o o f 75 : 25 .
Table 50-9 Insulin Pharmacodynamicsa
Insulin
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
Insulin lispro
¼
½–1½
4–5
Clear
Insulin aspart
5–10 min
1–3
3–5
Clear
Regular
½–1
2–4
5–7
Clear
NPH
1–2
6–14
24%
Cloudy
Lente
1–3
6–14
24%
Cloudy
Ultralenteb
6
18–24
36%
Cloudy
Insulin glargine
1.5
Flat
24
Clearc
a
The onset, peak, and duration of insulin activity may vary considerably from times listed in
this table. See text and Table 50-12.
b
Human Ultralente may have a shorter duration of action. Some patients require twice-daily
dosing.
c
The only extended-duration insulin that is clear. Should not be mixed with other insulins or
administered intravenously.
Long-Acting Insulins
U l t r a le n te in su li n i s a l on g - ac t in g i ns ul i n f o rm ul at i o n. Th is in su l in ha s a lo n g o ns e t o f a ct i vi t y
( 4 t o 6 h o u rs ) , a d e la ye d p e ak a c ti on ( 18 t o 2 4 ho u r s) , an d a p ro lo n ge d du r a ti o n o f a ct i vi t y ( 24
t o ≥ 36 h ou rs ) . Th is ti me c o u rs e o f a ct i vi t y i s n o t ve r y u s e f u l i n s up p re ss ing ac u te gl uc o se
c h al le n ge s r e la t ed to mea l s. H o we ve r , wh e n m im ic ki n g t he ph ys i ol og ic r ele a se of in su l in , l o ng a c ti n g i ns ul in ( us ed in co m bi n at io n re g im en s wi t h f r eq u en t , r a pi d t o s ho r t - a c ti n g i ns ul in
i n je c ti on s ) i s us e d t o s up p l y a l o w, “ ba sa l ” l e vel o f in su l in be t we e n m ea ls ( s ee Q u es ti o n 3 a n d
Ta b l e 50 - 13 ) . U nf o r tu na te l y, U l tr a le n te in su l in of te n r eq ui r es t wi c e - d ai l y ad m in is t r at io n to
a vo i d a “ pe ak ac ti o n, ” p ro vi d e 2 4 -h o u r co ve r a ge , a n d a ch i e ve a s mo o th eff e c t.
I n A p ri l 2 00 0 , i ns ul i n g lar g i ne ( La n tu s, A ve n ti s ) wa s a p p ro ve d b y t he F D A “ f o r on ce - da i l y S C
a d mi ni s t ra ti o n i n t he t r ea t me n t o f a d ul t a n d p ed ia t r ic pa t ie n ts ( ≥6 ye a rs ) wi t h t yp e 1 d ia be t es
m e ll i tu s o r a d ul t p a ti en t s wi t h t yp e 2 di a be t es wh o r e qu i re ba sa l (l on g - ac ti n g ) i ns ul i n f o r t he
c o nt r o l o f h yp e rg l yce mi a. ”
I n su l in gl a rg i ne is a n i nsu l in an a lo g i n wh ic h a spa r a gi n e i n p os it i on A 21 is su bs t it u te d wi t h
g l yc in e a n d t wo a r gi ni n es a re ad d ed to t he C - te rm i nu s o f t h e β - ch a in . Th is ch an g e i n t he am in o
a c id s e qu e nc e ca u se s a s h if t i n th e i so el e ct r ic poi n t f r om p H 5 . 4 t o 6 . 7, ma k in g i t m o re s o lu b le
a t an ac id ic p H . 5 6 O nc e i n je c te d , i ns ul in gl a r gi ne ( wh i c h i s a c l ea r s ol u ti on wi t h a p H of 4 .0 )
p r e ci pi t a te s a t p h ysi ol o gi c p H f o rmi n g a de po t tha t r el e as es i ns u li n s lo wl y o ve r 2 4 h ou r s. Th i s
r e s ul ts in de l a yed ab so rp t i on an d a le ss p r o no u nc e d p ea k c om pa r ed wi t h N P H i n su li n . 5 7 Z i nc
i s a d de d t o fu r th e r p r o lon g th e d u r at i on of in su l in g l ar g in e . I n c li ni ca l tr i als o f p at i en ts wi t h
t yp e 1 a nd t yp e 2 d i ab e te s , o nc e -d a il y i nj ec t io ns o f in su l in gl a rg i ne we r e a s e f f ec ti ve as N P H
i n lo we r i n g A 1 C val u es wi t h le ss no ct u r na l h yp og l yc em i a. 5 8
I n su l in de t e mi r ( N o vo Nor d i sk ) , a n e w b a sa l i ns ul in a na lo g be in g d e ve lo p ed , is e xp e ct e d t o b e
a va i la b le fo r us e i n 2 00 4. I ns u li n d e te mi r h as a f re e fa t t y ac id a tt ac h ed to t h e m ol ec u le ,
e n a bl in g i t to bi nd t o a lbu m in in th e s ub cu t an e ous t iss u e a nd bl oo d st r eam . Th is p ro du c es a
s l o w a nd co ns is t en t ra t e o f in su l in re l ea se .
Premixed Insulin
P r o d uc ts th a t c on t ai n p re m i xe d N P H an d r e gu l ar i ns u li n i n f i xe d r a ti os of 7 0 : 30 an d 5 0 :5 0 ; N P L
a n d i ns ul i n l is p ro in a f i xe d r at i o o f 7 5: 2 5; an d NP H a n d i ns ul in as p ar t in a f i xe d r at i on of 70 : 30
a r e a vai la b le fo r pa t ie n ts wh o h a ve di f fi cu l t y m eas u r in g a nd mi xi n g in su l ins . Th es e i ns u li ns ar e
c om p at i bl e wh e n mi xe d t o g e th e r a nd r et a in th e i r in d i vid u al ph a rm ac o d ynam ic p ro f il es (s e e
Q u e s ti o n 1 4 ) .
Treatment of Type 1 Diabetes: Clinical Use of Insulin
Clinical Presentation of Type 1 Diabetes
T h e U ni ve r s i t y S t u d e n t H e a l t h S e r vi c e re f e r s to t h e Di a be t i c C l i ni c A. H . , a s l en d e r , 1 8 ye a r - o l d w om a n w ho w a s r ec e n tl y d i s c h a r ge d f r o m t he h os p i ta l fo r seve r e d e h yd r a t i o n
a n d m i l d k e to a ci d os i s (n o r e co r d s a va i l ab l e ). A f a s t i n g an d a r a nd o m p l a sm a g l uc o se
o r d e r e d s u bs e qu e n tl y w e r e 1 90 mg / d L ( n o rm al , 7 0 t o 1 0 0) a nd 25 0 mg / d L (n o r ma l , 1 4 0 t o
< 2 0 0 ). Ap p r o x im a t el y 4 w e ek s b e f o re sh e w as h o s p it a l iz ed , A. H . h ad m o ve d ac r o ss t he
c o u n t r y t o a t t e n d co l leg e — h e r f i r s t t i me aw a y f r o m ho m e. I n r e t r os p ec t , sh e r em em b e rs
t h a t sh e h a d s ym p t o m s o f p ol yd i p s i a , n o c tu r i a ( s i x t i me s a n ig h t ) , f a t ig u e , a n d a 1 2 - lb
w e ig h t lo s s o ve r t h is pe r i o d , w h i c h s he a t t ri bu t e d to t he a nx i et y a s s o c i a te d w i th h e r
m o ve aw a y f r o m h o m e a n d a d j us t me n t to h e r n ew e n vi r o nm e n t. H e r m e d ic a l h i s to r y i s
r e m a r ka b le f o r re c u r r en t u p pe r r es p i r a to r y i n f e c t i on s a n d th r e e c as e s o f va g in a l
m o n i li a si s o ve r t h e p a st 6 mo n t hs . H e r f a mi l y h i s t o r y i s n e g a t i ve fo r d i a be t e s, a nd sh e
t a k es n o m ed i ca t i o ns .
P h ys i c a l e xa m in a t io n is w i t h i n n o rm a l l i mi t s . S h e w e ig h s 5 0 k g a n d is 5 ′ 4″ t al l .
L a b o r at o r y r e s u l t s a r e a s f ol l ow s : F P G , 28 0 mg / d L (n o r ma l , < 1 10 ) ; A 1 C , 1 4 % ( n o r m a l , 4 t o
6 %) ; t r a c e u r i ne ke t o nes a s m ea s u re d b y K e t o - D i a s t ix ( ne g a ti ve ) . O n th e ba s i s o f th e
a f o r e me n t io n ed h is t o r y a n d l a bo r a t o r y f i n d i n g s , t he p r es u mp t i ve di a gn o s is i s t yp e 1
d i a be t e s. W hi c h f i n di ng s a re c on s is t e n t w i t h t h i s di a gn o si s in A. H . ?
[ S I un i ts : F P G , 15 . 5 mmo l / L ( n or ma l , < 5 .6 ) ; A 1 C , 0 . 1 4 ( n or ma l , 0 . 04 to 0 .06 ) ]
A . H . me e ts s e ve r al o f the d ia gn o st ic c r i te r ia f or d i ab e te s . S h e h as c la ss ic s ym p to ms of t he
d i se as e (p ol yu r i a, po l yd ip s ia , we i gh t l os s , g lu co su r i a, f at i gu e , r e c u r re n t in f ec t io ns ) , a r an d om
p l as ma gl uc os e > 2 00 mg/ d L , a nd an F P G ≥ 1 2 6 m g /d L o n a t le as t t wo o cc as i on s 5 (s e e Ta b l es
5 0 - 1 a nd 50 - 2 ) . Th e el e va t e d A 1 C a ls o i s c on si st en t wi t h di ab e te s m el li t us . F e a tu r es o f A . H . 's
h i st o r y th a t a r e c on si st en t wi t h t ype 1 d ia b et es , in p a rt ic u la r , i nc lu d e t he r e l at i ve l y ac ut e o ns e t
o f s ym p to ms in ass oc i at io n wi t h a ma jo r li f e e ve nt ( mo vi n g a wa y f r o m h om e ) , ke t o ne s i n t he
u r i ne , ne ga t i ve f am il y h is t o r y, a n d a re la t i vel y yo u n g a g e a t o ns e t.
Treatment Goals
A. H . w i l l b e s t a r t ed o n in s u l in t he r a p y o n t h i s vi s i t . W ha t a re t he g oa ls o f th e r a p y? W i l l
n o r m o gl yc e m i a p r e ve nt t h e de ve l o pm e nt o r p ro g r e ss i o n o f lo n g - te r m c o m pl i ca t i o ns ?
I n t he ea r l y 1 9 90 s , mo st e n d oc ri n ol o gi st s we r e l ea n in g to wa r d n or mo g l yc em i a as an id e al go al
o f in su l in th e r ap y, al t ho ug h th e r e wa s st i ll s om e de b a te ab o ut th e re l at i on b e t we e n
h yp e r gl yc em i a a nd th e pr o g r es si on an d d e ve lo pm e nt o f l on g -t e rm co mp lic a ti o ns . A s d is cu ss ed
i n th e i n t ro d uc ti o n t o t his ch ap t e r , t he r es ul ts o f t h e D C C T c on vi nc in g l y de m on st r a te d th a t
l o we r i n g b lo o d gl u co se co n ce n t ra t io ns th r o ug h i nt e ns i ve i ns u li n t h e ra p y in p e rs on s wi t h t yp e 1
d i ab e te s s lo ws o r p r e ve nt s th e d e ve lo pm e nt of mic r o vas cu l a r co mp l ic at i ons . 21 Th u s, t he A D A
n o w a d vo ca t es “ ti g ht c o nt r o l , ” wh i c h i t d ef i ne s a s “ b l oo d g l uc os e l e vel s e qu a l t o o r be t te r th a n
t h os e a c hi e ved in t he i n te n si ve l y t re a te d g r o up in t h e D C C T t r ia l. ” 5 9
Th e o r ig i na l g o al of in t en s i ve i ns ul in t he r ap y i n th e D C C T wa s t o a ch i e ve g l uc os e l e vel s a s
c l os e t o t h e n on di a be t ic r a n ge
P . 5 0 -1 8
a s p os si b le . H o we ve r , eve n u nd e r i de a l s tu d y c on d i ti on s , t he in ve s ti ga t o rs we r e un a bl e t o
a c hi e ve t h es e i de a l t a rge t s i n t h e i nt e ns i ve i ns uli n th e r ap y g ro u p: t he m ea n A 1 C l e vel wa s 7. 2 %
( n o rm a l, 6% ) an d t h e m ea n bl oo d gl uc os e c on ce nt r a t io n wa s 1 55 mg / dL ( no r m al , < 1 00 ) . Th us ,
i n t en si ve in s u li n th e ra p y d o es n o t n ec es sa r il y l ead t o t h e a tt a in me n t o f e ug l yc em ia , a n d mo s t
p a t ie n ts wi l l r e qu i re in divi d u al i ze d g l yce mi c g oa ls . 44 , 5 9
I t is im po r t an t t o u n de r sta n d t h at in t en si ve in su l in t he r a p y i n vo l ves a co mp l e te p ro g ra m o f
d i ab e te s m an a ge me n t t ha t in cl u de s a b a la nc e d me a l p la n , e xe r c i se , d a il y b l oo d g l uc os e s el f m o ni t o ri ng , an d i ns ul i n ad j us tm e nt s b as e d o n t hes e fa ct o rs ( Ta b le 50 - 10 ) . B e ca us e th e p a ti en t
i s th e k e y m em be r of t he t e am , A. H . m us t be hi ghl y m o ti va t ed an d a bl e to l e a rn ab o ut t he
c om p le x m e t a bo li c i nt e r pl a y b et we e n in su l in an d li f es t yl e .
I n su mm a r y, A . H . i s a newl y d i a g n os ed pa t ie n t wi t h t yp e 1 d i ab e te s wh o ha s n o t yet de ve l op e d
a n y si g ns or s ym p to ms of l on g - te r m co mp l ic at i ons . Th e re f o re , s h e is an id e al ca n di da t e f o r
i n t en si ve in su li n th e ra p y a n d, if sh e i s wi l l in g and mo t i va te d , n or m og l ycem i a wi t h r a re
h yp o g l yc em ic r ea ct i on s is a r e as on a bl e l on g - te r m g o al . Th is g o al sh ou l d be ac h ie ve d g r a du al l y
o ve r se ve r a l mo n th s wi t h i n te ns i ve i ns u li n t h e ra py, d i e t, ed uc a ti o n, an d s tr o n g c li ni ca l s up p o rt .
I f A . H . i s u n wi ll i ng to pu rs u e su c h a ri go r o us a p p ro a ch at t hi s t im e o r i s u nwi l l i n g t o p e rf o rm
f r e q ue n t b lo od gl uc os e te s ts , a mo r e co n se r va ti ve a pp r oa ch wi l l h a ve to b e us ed . A d es i ra b le
g o al is an A 1 C va l ue as cl o se to t he no rm a l r a ng e a s p os si bl e wi t h ra r e h yp o gl yc em ic
r e a ct i on s. Ta b le 50 - 11 de sc r i be s t he id e al an d ac ce p ta b le m e t ab ol ic go a ls f or in t en si ve in s ul in
t h e r ap y.
Physiologic Insulin Therapy
W h a t m e t ho d s o f in s ul in a dm i n is t r a t io n a r e a va i l a bl e to ac h ie ve o p t im a l g l u co s e c on t r o l ?
Mo s t m e th o ds o f in su li n d e li ve r y u se d i n i n te ns i ve i ns ul in t he r ap y a r e d esi g ne d to m im ic
n o r ma l i ns ul i n se c re t io n a s c lo se l y as po ss ib l e ( th u s t he t er m “p h ysi ol o gic in su l in th e r ap y” ) . 60
P r o b le ms wi t h i ns u li n d eli ve r y i nc l ud e f ac t o rs th a t a f f ec t t he S C ab so r p ti on o f i n su li n ( Ta bl e
5 0 - 12 ) . Be f o re th e d e ve lo p me n t o f t h e r a pi d -a ct in g in su li n a n al o gs a n d in s ul in gl a r gi ne as a
b a sa l i ns ul i n, in su l in s l ac ke d p h a rm ac od yn am ic p r o fi l es th a t a ll o we d on e t o c l os el y si mu l at e
t h e b as a l -b ol us mo d el (se e te xt t h a t fo ll o ws ) . S om e a r g ue th a t e ug l yce mia is no t ac hi e vab l e
u n le ss in su li n i s a dm i ni st e r e d d ir ec t l y in t o t he por t a l vei n o r in a wa y t h a t b yp as s es t h e
p e r ip h e ra l ci r cu l at i on in i ti a ll y, t he r eb y m im ick i ng it s ph ys io lo g ic re l ea se in to t he po r t al
c i rc u la ti o n . A dm in is t e ri ng i ns ul in su bc u ta n eo us l y o r in t r a ven ou sl y p r od uce s p e r ip he r a l
h yp e r in su l in em i a a nd re la t i ve l y l o w l e ve ls o f in sul i n i n t h e h ep a ti c ve i n.
Table 50-10 Components of Physiologic Insulin Therapy
Multicomponent insulin regimen of basal plus preprandial insulin doses
Balance of carbohydrate intake, exercise, and insulin dosage
Daily, multiple self-monitoring of blood glucose levels
Patient self-adjustment of carbohydrate intake and insulin dosage with use of supplemental
rapid- or short-acting insulin according to a predetermined plan
Individualized target blood glucose and A1C levels
Frequent contact between patient and diabetes team
Intensive patient education
Psychologic support
Regular objective assessment (as measured by A1C)
A1C, glycosylated hemoglobin.
Modified from reference 76.
C l i ni ci a ns no w h a ve m o re t oo ls t o mi mi c p an c re at i c r e le as e o f th e h o rm one . I n t he no n di ab e ti c
i n di vi d ua l , t he pa n cr e as s ec r e te s b ol us e s o f i ns uli n in re s po ns e t o s na ck s a n d m ea ls . Be t we e n
m e al s a nd th r o ug h ou t t he n ig h t, t he pa nc r ea s s ec r e te s sm a ll am ou n ts o f i n su li n th a t a r e
s u f fi ci en t to s u pp r es s l ipo l ys is a n d h ep a ti c g lu cos e o u tp u t ( b as al in su l in ) . T wo m e th o ds h a ve
b e e n us e d t o a ch ie ve a s im i la r p a t te r n o f i ns u li n r e l ea se : (1 ) in su l in pu mp t h e ra p y ( p re vi ou sl y
r e f e r re d t o a s “c on t in uo us S C in f us io n o f i ns u li n ” ) ( F i g. 50 - 4 ) a nd ( 2 ) mu l tip l e d ai l y do s es o f
i n su li n (s ee Q u es ti o n 4 ) .
Insulin Pump Therapy
Th e u se o f a n i ns ul in pum p i s c ur r e nt l y t he m os t p r e ci se wa y t o m im ic no rm a l i ns ul in se c re t io n .
Th i s co ns is ts o f a b a tt e ry - o p e r at e d p um p a nd a co m pu t e r t ha t c a n p ro g r am t he pu mp to de l i ver
p r e de t e rm in e d am o un ts o f r eg u la r i ns u li n , i ns ul in l is p ro , o r i ns ul i n as pa r t f r o m a re se r vo i r t o a
s u bc ut a ne o us l y i ns e r te d c a th e te r o r n ee dl e (e . g ., Me d t r o n i c Mi n i Me d 5 0 8 , P a r a di gm 51 2 ,
N o r t h ri d ge , C al i fo r ni a a nd A n im as I R 1 00 0 , F r a zer , P A ) . 61 , 62 Th es e s ys tem s a r e p o rt a bl e a n d
d e si g ne d t o d e li ve r va ri ou s b as a l am o un t s o f i ns ul i n t h ro u gh o ut t he da y as we l l as me al r e l at e d b ol us es p ro vi d ed b y r e gu l ar in su l in , i ns u lin l is pr o , o r in su li n a sp a rt . A bo lu s o f re g ul a r
i n su li n c an b e r el e as ed b y t h e p a ti en t 30 m i nu t es be f o re fo o d i ng es t io n . I n su l in as pa r t i s F D A
a p p ro ve d fo r us e i n t he in s ul in pu m p a nd ap p ro va l of in su l in li sp r o is pe nd i ng . 61 I f r a pi d -a c ti ng
i n su li ns a re us ed , m e al - re l a te d b ol u se s a re gi ve n 0 t o 1 5 mi n ut es be f o re e a t in g .
Th e p r e fe r r ed me al pl a nn i ng ap p r oa ch fo r pa t ie nt s us in g a n i ns ul i n p um p i s c a rb o h yd ra t e
c o un t in g . Th e “ in su li n to c a r bo h yd ra t e r a ti o ” o r how m u c h c a rb o h ydr a te is c o ve r ed b y 1 un i t o f
i n su li n m us t b e d e te r mi ne d . Th is c a lc ul a ti on ca n b e ba se d o n t h e “ 5 00 R ul e . ” Th e n um be r 50 0
i s d i vi de d b y t he t ot a l d ai l y d os e o f i ns ul i n t he pat i e nt is u s in g t o d e te r mi ne t he in su l in to
c a r bo h yd ra t e r a ti o (s ee Q u e s ti o n 1 7 ) . Th e b as a l i n su li n i n fu si o n
P . 5 0 -1 9
r a t e m a y be ad ju s te d d ep e n di ng on t he s i tu a ti o n. Ma n y p a t i en t s f in d i t a dva n t a ge o us to
d e c re as e t h e b as al r at e d u r in g th e m id dl e o f th e n i gh t wh e n n oc t u rn a l h yp o gl yc em i a is m o st
l i ke l y to oc cu r . Th e b as al r a te al so m a y be in c re as e d b ef o r e a wa k en i ng to a vo i d h yp e rg l yce mi a
d u e t o th e “ d a wn ph e nom e no n ” —a d ju st me n ts tha t a re no t p o ss ib le us in g c on ve n ti o na l i ns u li n
r e g im en s . F ea t u re s o f t he cu r r en t pu mp m o de ls in c lu d e r em o te p ro g ra mmi n g c ap a bi li t ie s t o
a d mi ni s te r or su sp e nd ins u li n d el i ve r y; th e c ap a bi l it y t o p r o g ra m mu l ti pl e , p a ti e nt - sp ec i fi c
d e li ve r y p a tt e rn s ; a l o w - vo l u me al e r t; an op t io n al vi b r a te m o de ; a n d a c h ild - b lo ck fe a tu r e t o
r e s t ri ct p ro g ra mm in g . The H e al t h C a r e F in a nc in g A d m in is t ra t io n ( H C F A) an n o un ce d i n
S e p t em be r of 19 9 9 t ha t Me d i c a r e n o w c o ve rs i nsu l in in f us io n p um p s f o r el i gi b le be ne f ic ia r i es
wi t h t yp e 1 d ia be t es . Fac t o rs to c o ns id e r wh e n ch o os i ng a p um p i nc lu de s a fe t y f ea t u re s,
d u r ab i li t y, a b il i t y o f th e m a nu f ac tu r e r t o p r o vi de s e r vic e , a va il a bi li t y o f t ra i ni n g, cl in ic a ll y
d e si r ab l e f ea t u re s a nd co sm e ti c a t t ra ct i ve ne ss for t h e us e r . 6 1 , 6 3
Table 50-11 Goals of Intensive Insulin Therapya
Target Blood Glucose Values
Ideal (mg/dL)b
Acceptable (mg/dL)c Pregnancy (mg/dL)
Fasting
70–120
70–140
60–90
Preprandial
70–105
70–130
60–105
1 hr postprandial
100–160
100–180
110–130
2 hr postprandial
80–120
80–150
90–120
2–4 AM
70–100
70–120
>60
A1C
<6%
<7%
<6%
Urine ketonese
Absent
Rare
Rare
a
Modified and extrapolated from references 21 and 65. Intensive insulin therapy is a
complete therapeutic program of diabetes management and requires a team approach (see
Table 50-10).
b
Ideal values approximate those ssen in nondiabetic individuals and are included for
illustrative purposes only.
c
Acceptable values should be individualized to levels that are attainable without creating
undue risk for hypoglycemia. These results are similar to the results achieved in the DCCT
trial. These values may be inappropriate for patients with hypoglycemic unawareness,
counter-regulatory insufficiency, angina pectoris, or other complicating features (see Table
50-15).
d
A1c, glycosylated hemoglobin. Normal values vary; normalize to laboratory.
e
Does not apply to type 2 diabetes patients.
Table 50-12 Factors Altering Onset and Duration of Insulin Action
Factor
Route of
Administration
Comments
Onset of action more rapid and duration of action shorter for
IV>IM>SC106,292,293
Intrapulmonary insulin has more rapid onset and shorter duration
than SC insulin, resembling IV pharmaco-kinetics50, 294, 295
Factors Altering Clearance
Renal function
Renal failure ↓ insulin clearance. May prolong and intensify action
of exogenous and endogenous insulin
Insulin antibodies
IgG antibodies bind insulin as it is absorbed and release it slowly,
thereby delaying and/or prolonging its effect49
Thyroid function
Hyperthyroidism ↑ clearance, but also ↑ insulin action, making
control difficult. Patients stabilize as they become euthyroid296
Factors Altering SC
Absorption
Factors that ↑ SC blood flow ↑ absorption rates of regular insulin.
Effect on intermediate- and long-acting insulins minimal
Site of injection
Rate of absorption fastest from the abdomen, intermediate from
the arm, and slowest from the thigh.70 Less variation observed in
type 2 patients. Less variation observed with lispro insulin
Site
Half-Life Absorption (min)
Abdomen
87 ± 12
Arm
141 ± 23
Hip
153 ± 28
Thigh
164 ± 15
Exercise of injected
area
Strenuous exercise of an injected area within 1 hr of injection can
↑ absorption rate. Rate of absorption of regular insulin ↑, but little
effect on intermediate-acting insulin50,296
Ambient
temperature
Heat (e.g., hot weather, hot bath, sauna) ↑ absorption rate. Cold
has opposite effect47, 50
Local massage
Massaging injected area for 30 min substantially ↑ absorption rate
of regular insulin as well as longer- acting insulins296
Smoking
Controversial. Vasoconstriction may ↓ absorption rate50
Jet injectors
Insulin absorption more rapid, probably secondary to ↑ surface
area for absorption297
Lipohypertrophy
Insulin absorption is delayed from lipohypertrophic sites72
Insulin preparation
More soluble forms of insulin are absorbed more rapidly and have
shorter durations of action (see Table 50-9 and text). Human
insulin may have shorter action than animal insulin
Insulin mixtures
The short-acting properties of regular insulin may be lost if mixed
with Lente insulins (see Question 14)
Insulin
concentration
More dilute solutions (e.g., U-40, U-10) are absorbed more rapidly
than more concentrated forms (U-100, U-500)47
Insulin dose
Lower doses are absorbed more rapidly and have a shorter
duration of action than larger doses
IgG, immunoglobulin G; IM, intramuscular; IV, intravenous; SC, subcutaneous.
Implantable Insulin Pumps
R e m o te -c o nt r o ll ed im pl an t a bl e p um ps th a t d el i ver i ns ul i n i nt r a ve no us l y o r i n t ra p er i to n ea ll y a r e
u n d er st u d y. 6 4 In su li n i s s t or e d i n a l a r ge re s er vo i r th a t is su r gi ca l l y i ns er t e d s ub cu t an e ou sl y
i n t o t he ab d om en o r ch es t wa l l . P r ob l ems t ha t h ave d e la ye d d e ve lo pm e nt i n cl ud e e xp e n s e ,
l o ca l e r os io n , i n fe ct i on , a n d c at h et e r b l ock a ge . Th e Me d t r o ni c Mi n i Me d 2 0 0 7 i mp la n ta b le
i n su li n p um p i s a p pr o ve d f o r s al e i n Eu r o pe ; h o we ve r , it ha s n o t ye t be en c le a r ed fo r m a rk e ti n g
i n th e Un i te d S ta t es .
Multiple Daily Injections
H ow c a n i n su l i n i n je c t io n s be ad m in i s te r e d t o A. H . i n a w a y t h a t m i mi c s th e ph ys i o l o g i c
r e l e as e of i ns u l in f r om t h e pa n c re a s?
E n d oc r in o lo gi s ts h a ve de ve l o pe d a va ri e t y of in su l in r eg im e ns th a t a re int e n de d t o m im ic th e
r e l ea se o f i ns ul in f ro m t he p an c re as . 65 E xa m p le s o f th es e a r e d is pl a ye d in Ta b l e 5 0 -1 3 a nd
i l lu s tr a te d i n Fi gu r e 5 0 -5. A t ot a l d ai l y do se of ins u li n i s es t im a te d e mp i ric a ll y ( e .g . , 0 . 5 U / kg
p e r da y) o r a cc o rd in g to g u id e li n es s im il a r t o t h os e l is t ed in Ta b le 50 - 1 4. Th e t o t al d a il y d os e
o f in su l in th e n is sp li t i n to se ve r a l d os es . I n g e ner a l , t h e b as al do se co mpr i s es a p pr o xi m a t el y
5 0 % o f th e t o ta l d a il y d os e .
A r e gi me n th a t is be co min g le ss c om mo n l y u se d in vo l ve s i nj ec t in g a m i xt u r e o f i nt e rm e di a te a c ti n g a nd r eg ul a r i ns u lin t wi c e d ai l y be f o re b re ak f as t a n d b ef o r e d in ne r . ( S e e Fi g . 5 0 - 5 A a n d
Me t h o d 1 i n Ta bl e 5 0 - 13. ) Th e mo r ni n g d os e o f re g ul a r i ns u li n i s i nt e nd ed t o t ak e c a re of t he
b r e ak f as t m ea l ; t he m o r ni n g d os e o f N P H t ak e s ca r e of t h e n o on me al and p r o vid es ba sa l
i n su li n th r ou g ho u t t he day; t h e e ve n in g d os e o f reg u la r in su l in ta ke s c ar e o f t he e ven in g m ea l ;
a n d t h e e ve ni n g d os e o f N P H p r o vi de s b as al in sul i n l e vel s d u ri n g t he ni g ht a nd t ak es c a re of
a n y e ve ni n g sn ac k t h at is in g es te d . Be ca us e p a tie n ts
P . 5 0 -2 0
i n th e D C C T u se d t h re e to f ou r in je c ti o ns p e r d a y t o ac hi e ve ti gh t c o nt r o l, t h is t wi c e -d ai l y
m e th o d o f N P H a nd r eg ul a r i ns u li n a dm i ni st r a ti on i s n o l on g e r co ns i de r ed “ i n te n si ve in su li n
t h e r ap y. ” H o we ve r , t wi ce - d a il y r e gi me ns m a y b e e f f ec t i ve f o r a s ho r t p e r io d of ti m e in n e wl y
d i ag n os ed t yp e 1 d i ab e tic pe r so ns wh o a re st i ll pr o d uc in g a si gn i fi ca n t am o un t o f in su li n , s uc h
a s A . H. R eg u la r in su li n is o ft e n r ep l ac ed b y in su li n li sp r o o r i ns u li n a sp a r t i n t h is re g im en ,
b e ca us e th e y ar e b o t h mo r e ra p id ac ti n g. H o we ve r , b ec au se t he i r d u ra t io n o f ac ti o n is s h o rt e r
t h a n t ha t of r eg ul a r i ns u li n , d os es o f N P H ma y h ave t o be in cr e as ed t o min i mi ze p re p ra n di al
h yp e r gl yc em i a.
FIGURE 50-4 Insulin infusion pumps: comparison of
closed-loop and open-loop systems. (Used with permission
from reference 298.)
View Figure
F i g ur e 5 0 - 5 B d ep ic ts a va r i at i on of t he af o r em en t i o ne d m e th o d. I t is th e sa m e e xc e p t t h at t he
e ve n i ng do se of in t e rm ed i a te - ac t in g i ns ul i n is give n as a t h ir d i n je ct i on at b ed t im e ( se e Me t h o d
2 i n Ta b l e 5 0 - 1 3 ). Th i s sh i f ts th e t im e o f pe ak ef fe c t f r om ap p ro xi m a t el y 2 t o 3 A M t o
a p p ro xi m a t el y 7 A M. B y a d mi ni s te r in g th e i nt e rme d ia t e -a c ti ng in su l in at be d t im e, no c tu r na l
h yp o g l yc em i a is r ed uc e d a n d p ea k i ns ul i n ac t i vit y o cc u rs wh e n t h e p at i en t i s m or e l ik e l y to be
a wa k e an d i n ge st i ng fo od . Th i s me t ho d m a y be us e fu l fo r p a ti e nt s i n wh om no c tu r na l
h yp o g l yc em i a a nd fa s ti ng h yp e rg l yce mi a a r e p a rti c ul a rl y t r ou b le so me .
F i g ur e 5 0 - 5 C s ho ws t he t h e o re t ic al ef f e c t p r o vid ed b y t hr e e e qu a l d os es of r e gu l ar o r i ns ul i n
l i sp r o ( o r i ns u li n a sp a rt ) b e f o re m e al s a nd a d os e o f i n te r me d ia t e -a ct i ng in s ul in a t b ed t im e t o
p r o vi de ba sa l i ns u li n l e ve l s d u ri ng t he ni gh t (s ee Me t h o d s 3 an d 4 in Ta b le 5 0 -1 3 ). Th i s
r e g im en gi ve s t h e p at i ent m or e fl e xi b i li t y in bo t h t h e ti mi ng a n d th e s i ze of m ea ls . Al t ho ug h th e
r e g im en sp ec i fi es eq u al d o se s, t he c a r bo h yd ra t e c o nt e nt o f t he me al as we l l a s p r ep r an d ia l
b l oo d g l uc os e val ue s u l tim a te l y de t e rm in es t he se d os es ( se e Qu e st io n s 18 a nd 19 ) . I n s om e
p a t ie n ts , i na d eq u at e b asa l in su li n d u r in g t h e d a y r e s ul ts in p re p ra n di al h yp e r gl yc em ia as th e
e f f ec ts o f in s ul in li sp r o , a s pa r t o r r eg ul a r i ns ul i n wa n e .
A n a lt e rn a ti ve t ha t i s g ain i ng in po p ul a ri t y is th e u s e o f a lo ng - ac t in g i ns ul i n ( U l t ra l en t e o r
i n su li n g l a rg in e ) i n t h e mo r n in g o r e ven i ng to p rovi d e ba sa l i ns u li n l e vel s t h r o ug ho u t t h e d a y,
a l on g wi t h d os es o f r eg ul a r o r in su l in li sp r o o r a sp a r t b e fo r e m ea ls (s e e Fi g . 5 0 - 5 C) . Th is
m e th o d t he o r et ic a ll y p rovi d e s i ns ul in in e xa c t l y th e s am e wa y a s t h e i ns ul i n p um p ( b as al le ve ls
p l us s ma l l b ol us es fo r me a ls an d s na ck s ). In do in g
P . 5 0 -2 1
s o , i t o f fe r s s om e o f t he s am e a d va n ta ge s o f th e p u mp in th a t i t p e rm i ts so m e d eg r ee o f
f l e xi b i li t y in t he pa t ie n t 's l i fe st yl e . F o r e xa m p l e, if a pa t ie n t wi t h d ia be t es c h oo se s t o s ki p a
m e al , h e o r s h e o mi ts a p r e me al bo l us ; i f t h e p at ie n t c ho o se s t o e at a l a rge r me a l t ha n u su a l,
h e o r sh e i nc r e as es th e p r e me al bo l us . Sim i la r do s e a dj us tm e n ts c a n be m a de to ac co mm od a te
s n ac ks , e xe r c is e p a t te r ns , an d a cu t e i ll ne ss es . Th e e xc e ss zin c i n U l t ra l en t e b i nd s r e gu la r
i n su li n , b u t n ot in su l in lis p r o; th e r ef o r e, r eg ul a r a n d Ul t r al en t e i ns ul i ns sh o ul d b e ad mi ni s te r ed
i n s e pa r a te s yr i n ge s. Fu rt h e rm o re , to mi ni mi ze the
P . 5 0 -2 2
“ p e ak ” e f f ec ts of U l tr a le nt e an d to en su r e 2 4 -h o ur b as a l i ns ul in le ve ls , t wic e - da il y
a d mi ni s t ra ti o n m a y b e ne e d ed . I ns u li n g l ar g in e ap p e ar s t o b e ha ve m o r e l ik e a t ru e b a sa l
i n su li n b ec a us e i t l ac ks a “ p ea k e ff e ct . ” I t m us t , h o we ve r , b e i nj ec t ed s e pa r a t el y.
Table 50-13 Examples of Various Insulin Regimens
AM
Noon
PM
Bedtime
Comments
Method 1
Reg/NPH
—
Reg/NPH
Reg/Lente
Reg/Lente
Lispro/NPH
Lispro/NPH
Lispro/Lente
Lispro/Lente
Aspart/NPH
Aspart/NPH
Aspart/Lente
Aspart/Lente
—
This regimen
relies on the
AM NPH or
Lente to cover
the noon meal
and to provide
basal insulin
during the day.
The evening
NPH or Lente
supplies basal
insulin during
the night.
However, the
evening NPH
has peak
activity at ≍
2–4 AM when
plasma glucose
is at a
physiologic
nadir,
predisposing
the patient to
nocturnal
hypoglycemia.
Empirically,
some clinicians
use a 1:2 ratio
of Reg:NPH. If
insulin lispro
or insulin
aspart is used,
we recommend
basing the dose
on an empiric
insulin
unit:grams
carbohydrate
ratio of 1:15
initially. See
Table 50-14.
Method 2
Reg/NPH
—
Reg
NPH
Reg/Lente
Reg
Lente
Lispro/NPH
Lispro
NPH
Lispro/Lente
Lispro
Lente
Aspart/NPH
Aspart
NPH
Aspart/Lente
Aspart
Lente
Method 3
See notes for
Method 1. By
shifting the
NPH or Lente
dose to
bedtime, the
peak action
occurs in the
early morning
(5–7 am),
when the
patient is
awake and
ready to eat.
This also
corresponds to
the dawn
phenomenon, a
natural rise in
the plasma
glucose from
growth
hormone. See
Method 1
comments for
empirical
doses.
Reg
Reg
Reg
NPH
Reg
Reg
Reg
Lente
Reg
Reg
Reg
Glargin
e
Reg
Reg
Reg
Ultralen
te
These methods
provide
premeal
boluses of
insulin. The
evening dose
of NPH, Lente,
ultralente, or
insulin
glargine
provides basal
levels at night
to prevent
lipolysis and
suppress
glycogenolysis
and
gluconeogenes
is. Often, the
intermediateor long-acting
insulins must
be given twice
daily to
provide
sufficient basal
insulin
throughout the
day. When
insulin
glargine
(Lantus)
replaces two
injections of
NPH or Lente,
the initial dose
should be
reduced by
20% from the
previous day's
total daily dose
of
intermediateacting insulin.
See regimens
for Method 4.
Method 4
Lispro/NPH
Lispr
o
Lispro
NPH
Lispro/Lente
Lispr
o
Lispro
Lente
Lispro
Lispr
o
Lispro
Glargin
e
Aspart/NPH
Aspa
rt
Aspart
NPH
Aspart/Lente
Aspa
rt
Aspart
Lente
Aspart
Aspa
rt
Aspart
Glargin
e
Insulin lispro
or insulin
aspart is
substituted for
regular insulin
in Method 3.
Postprandial
values are
lower, but one
may see
preprandial
hyperglycemia
because the
duration of
action is too
brief to supply
sufficient
levels of basal
insulin during
the day. To
address this
issue, some
clinicians are
combining
lispro with
regular insulin
or very low
doses of
intermediateacting insulin
before meals
(1 unit/hr).
When insulin
lispro or
insulin apart is
used as the
mealtime
insulin, a
minimum of
two injections
of
intermediateacting insulin
is required.
When insulin
glargine
(Lantus)
replaces two
injections of
NPH or Lente,
the initial dose
should be
reduced by
20% from the
previous day's
total daily dose
of
intermediateacting insulin.
See Method 6.
Empirically,
the lispro dose
is based on the
estimated CHO
intake (1
unit/15 g). See
Table 50-14.
Method 5
Reg/Ultralent
e
Reg
Reg/Ultralent
e
Lispro/Ultrale
nte
Lispr
o or
Lispro/Ultrale
nte
Aspart/Ultrale
nte
Aspa
rt
Aspart/Ultrale
nte
—
Because
human
Ultralente has
a relatively
short duration
of action, it
must be dosed
twice daily to
maintain
smooth basal
concentrations.
However,
because its
onset is slow, a
short-acting
insulin must be
given before
the noon meal.
Ultralente can
be given at
approximately
50% of the
total daily dose
with half of the
dose given
before
breakfast and
the other half
given before
dinner. Insulin
glargine
(Lantus),
another longacting insulin,
cannot be
mixed with
other insulins
because its
pharmacodyna
mic profile
could be
altered. It may
be given once
daily.
Method 6
Reg/Ultralent
e
Reg
Reg
NPH
Lispro/Ultrale
nte
Lispr
o or
Lispro
NPH
Some patients
achieve better
control of
fasting
hyperglycemia
Aspart/Ultrale
nte
Aspa
rt
Aspart
NPH
by using NPH
at bedtime to
target earlymorning
insulin
resistance
while
continuing to
take Ultralente
each morning.
Reg, regular insulin.
View Figure
FIGURE 50-5 Theoretical insulin effect provided
by various insulin regimens. A. Two daily
injections of short-acting (regular, lispro, insulin
aspart) and intermediate-acting insulin (NPH or
Lente). B. Morning injection of short-acting insulin
and an intermediate-acting insulin, a presupper
injection of short-acting insulin, and a bedtime
injection of intermediate-acting insulin. Suggested
for patients with early-morning hypoglycemia
followed by rebound hyperglycemia or for patients
with early-morning hyperglycemia (rebound
phenomenon). C. Preprandial injections of shortacting insulin and intermediate-acting insulin at
bedtime. A long-acting insulin (insulin glargine) may
be used in place of intermediate-acting insulin. D.
Preprandial injections of short-acting insulin and
intermediate-acting insulin at breakfast and bedtime.
E. Continuous subcutaneous insulin infusion. B,
breakfast; HS, bedtime snack; L, lunch; S, supper.
Arrows, time of insulin injection (30 minutes before
meals). (Adapted from reference 291.)
S h o u l d A. H . u s e a n i n su l i n p u m p o r mu l t ip l e in s u l in i nj e c ti o ns ?
I n d ic at i on s f o r i nt e ns i ve i n su li n th e ra p y a re li st e d i n Ta bl e 5 0 -1 5 . As d is cus se d p r e vi ou sl y,
A . H . is an id e al c a nd id a te f o r i nt e ns i ve i ns ul i n t he r a p y. Sh e i s n e wl y d ia gn o se d , h as no t yet
d e ve l op ed t he lo ng - t e rm c om p li ca t io ns of di a be t es , an d s ho ul d d e r i ve t he p o t en t ia l b en e fi t s o f
n o r mo gl yc em ia . As su mi ng A . H . wi l l b e a bl e t o c om p l y wi t h i n te ns i ve i ns uli n th e r ap y,
i n di vi d ua li ze d ta r ge t bl oo d gl uc os e l e ve ls t h a t str i ve f o r t he be s t l e vel of g l uc os e c on t r ol
p o ss ib l e wi t h o ut pl ac i ng h e r at un d ue ri sk fo r h ypo g l yce mi a s ho u ld be p res c ri b ed . Sh e m us t b e
wi l l i n g t o t es t he r b l oo d g l uc os e c on ce n t ra t io ns fo u r or mo r e t im es da il y an d in je c t h e rs el f
t h r e e t o f ou r ti me s d ai l y o r le a r n a bo u t t he us e an d c a r e o f a n i ns ul i n p um p . S h e a ls o m us t b e
wi l l i n g t o k ee p d e ta il e d re c o rd s a nd pa r t ic ip a te in a n e xt e n s i ve e d uc at i on p r o g ra m t ha t en a bl es
h e r to ad j us t h e r i ns ul in d o se s b as ed on bl o od glu c os e c on ce n t ra ti o ns , ph ys ic a l ac t i vi t y, a nd
t h e c a rb o h yd ra t e co n te n t o f he r s na ck s a nd me als .
P a t i en ts mu st be ab l e t o a t t ai n t h e a bo ve sk il ls be f o r e t he y a r e co n si de r ed vi a bl e u se r s o f a n
i n su li n p um p . Th e A D A re c omm e nd s t h at th e u s e o f i n s u li n p um ps be li mit e d to hi gh l y
m o ti va t ed in d i vid u al s u nd e r th e g u id an ce o f a h ea l t h ca r e t e am t ra in e d an d k n o wl e dg e ab le in
t h e ir us e . P um ps o ff e r t he p at i en t fl e xi b i li t y wi t h m e al s ch e du l es a n d t r a ve l . Mo s t s tu d ie s h a ve
s h o wn t ha t p um p t h e ra py p r o vi d es e q ui va l en t a nd so me t im es be t te r gl yce m ic c on t r ol th a n d oe s
i n t en si ve m a na g em en t wi t h m ul t ip l e in j ec ti o ns . 61 , 6 6
Table 50-14 Empiric Insulin Doses
Estimating Total Daily Insulin Requirements
These are initial doses only; they must be refined using SMBG results. Patients may be
particularly resistant to insulin if their blood glucose concentrations are high (glucose
toxicity); once glucose concentrations begin to drop, insulin requirements often decrease
precipitously. The weight used is actual body weight. Insulin dose requirements can change
dramatically over time depending on circumstances (e.g., a growth spurt, modest weight
gain or loss, illness).
Type 1 Diabetes
Initial dose
0.5–0.8 U/kg
Honeymoon phase
0.2–0.5 U/kg
With ketosis, during illness, during growth
1.0–1.5 U/kg
Type 2 Diabetes
With insulin resistance
0.7–1.5 U/kg
Estimating Basal Insulin Requirements
These are empiric doses only and should be adjusted using appropriate SMBG results
(fasting or premeal). Basal requirements vary throughout the day, often increasing during
the early morning hours. The requirement also is influenced by the presence of endogenous
insulin, the degree of insulin resistance, and body weight. The range is 0.3 to 1.4 U/hr.
Approximately 50% of total daily dose
Approximately 0.7 U/hr for a 70-kg person (154 lb)
Estimating Premeal Insulin Requirements
The “500 Rule” estimates the number of grams of carbohydrate (CHO) that will be covered
by 1 unit of rapid-acing insulin.56 The rule is modified to the “450 Rule” if using regular
insulin.
500/total daily dose of insulin (TDD) = number of grams covered
Example: For a patient using 50 units per day, 500/50 = 10. Therefore, 10 g carbohydrate
would be covered by one unit of insulin lispro or insulin aspart. This equation works very
well for type 1 patients in estimating their premeal insulin requirements. Because patients
with type 2 diabetes have insulin resistance, the rule may underestimate their insulin
requirements.
Determining the “Correction Factor”
Supplemental doses of rapid-acting insulin are administered to acutely lower glucose
concentrations that exceed the target glucose concentration. These doses must be
individualized for each patient and again are based on the degree of sensitivity to insulin
action. For example, if the premeal or bedtime blood glucose target is 140 mg/dL and the
patient's value is 190 mg/dL, additional units of insulin might be added to the premeal dose
or an additional supplemental bedtime dose of lispro might be given. The correction factor
determines how far the blood glucose drops per unit of insulin lispro or insulin aspart given
and is known as the “1800 Rule”.65 For regular insulin, the rule is modified to the “1500
Rule”. The equation is as follows:
1800/TDD = point drop in blood glucose per unit of insulin
Example: If a patient uses 30 units of insulin per day, their correction factor (or insulin
sensitivity) would be 1800/30 = 60 mg/dL. Therefore, the patient can expect a 60 mg/dL
drop for every unit of rapid acting insulin administered. Patients with a higher sensitivity
factor have lower insulin requirements. Individuals with a lower sensitivity factor (higher
insulin requirements) typically achieve a smaller reduction in blood glucose per unit of
insulin.
CHO, carbohydrate; SMBG, self-monitored blood glucose; TDD, total daily dose.
Adapted from reference 60.
Table 50-15 Intensive Insulin Therapy: Indications and Precautions
Patient Selection Criteria
Type 1, otherwise healthy patients (older than 7 yr of age) who are highly motivated and
compliant individuals. Must be willing to test blood glucose concentrations four times daily
and inject three to four doses of insulin daily
Diabetic women who plan to conceive
Pregnant diabetic patients
Patients poorly controlled on conventional therapy (includes type 2 patients)
Technical ability to test blood glucose concentrations
Intellectual ability to interpret blood glucose concentrations and adjust insulin doses
appropriately
Access to trained and skilled medical staff to direct treatment program and provide close
supervision
Avoid or Use Cautiously in Patients Who Are Predisposed to Severe Hypoglycemic
Reactions or in Whom Such Reactions Could Be Fatal
Patients with counter-regulatory insufficiency
Type 1 diabetes for ≥15 yr (not all patients)
β-Adrenergic blocker therapy
Autonomic insufficiency
Adrenal or pituitary insufficiency
Patients with coronary or cerebral vascular disease
(Note: Counter-regulatory hormones released in response to hypoglycemia may have
adverse effects in these individuals)
Unreliable, noncompliant individuals, including those who abuse alcohol or drugs and those
with psychiatric disorders
P . 5 0 -2 3
I n su l in pu mp s a r e p a rt icu l a rl y u se f ul i n pa ti e nt s wi t h f r e qu e nt , un p re d ic tab l e h yp o gl yc em ia or
m a rk e d d a wn ph e no me na ( se e Q ue st i on 19 ) . O the r s h a ve d es c ri b ed th e m e th o ds b y wh i c h
i n su li n d os e s a re es t ab lis h ed an d a l te r ed in pa t ien t s u si ng t he in su li n p ump . 6 0 , 6 3 S i nc e A . H .
h a s j us t b ee n d i ag n os ed, s he s h ou ld be in i ti a te d o n m u lt i pl e d ai l y do se s of i ns ul i n a t t hi s t im e .
O n c e s he ha s a cq ui r e d th e se s ki l ls , s he m a y be c o ns id e re d fo r pu mp th er a p y.
Clinical Use of Insulin
Initiating Insulin Therapy
H ow s h o ul d mu l t ip l e -do s e in s ul i n th e r ap y b e i n i t i at e d i n A. H . ?
Th e r e is no ge n er a ll y acc e pt e d a pp r o ac h t o t he in i t ia t io n o f m ul t ip le - d os e i ns u li n t h er a p y in
n e wl y d i a gn os e d p at i en ts . A c on se r va t i ve t o ta l da i l y do se of in su l in is e s ti m at e d em p i ri ca ll y o r
a cc o r di ng t o g ui de l in es si m il a r t o t h os e l i s te d i n Ta b le 50 - 1 4. S om e e nd ocr i n ol o gi st s p r ef e r t o
b e gi n wi t h N P H , o pt im i ze t he N P H do se s , a nd the n ad d ra pi d o r s h o rt - ac ti n g i ns ul i n i f n ee d ed
l a t er . Th e to t al da il y d ose o f N P H is sp li t i n it i al l y i n t o t wo d os es : t wo - t hi r ds in t he m o rn i ng an d
o n e - th i rd be f o re di nn e r . O t h e r s i ni ti a te t he pa t ie nt o n m i xe d do se s o f N P H a n d r e gu la r in su li n
t wi c e da i l y. On an o ut p ati e n t b as is , t h is l a tt e r a p pr o a ch m a y be so me wh a t i m p ra ct ic a l in t ha t
t h e p a ti e nt wi l l h a ve to le a r n h o w t o m i x i n su li ns i n ad di t io n to s e ve r al ot he r sk il ls on th e fi rs t
vi s i t . O n e a ls o s ho ul d b e a wa r e t ha t ad mi ni s tr a ti on o f t wo - t h i rd s o f t h e d os e i n th e m or n in g
a ss u me s co ns um p ti o n o f t wo - t h i r ds o f th e t o ta l da i l y c a r bo h yd ra t es at b rea k fa s t a nd lu nc h .
Th i s ma y n ot ho l d t r ue for m an y p a ti en t s.
I n su l in gl a rg i ne (L a n tu s) m a y al so be us ed as a b a sa l i ns ul i n wi t h b ol us d o se s o f a r ap id - o r
s h o rt - ac t in g i ns ul i n ( i ns ul i n l is p ro , i ns u li n a sp a r t, o r r eg u la r ) g i ve n wi t h mea l s. S tu d ie s h a ve
s u gg es t ed t ha t t h e b as al i ns u li n p r of i le ob t ai n ed fr o m
P . 5 0 -2 4
g l a rg i ne is s up e r io r to NP H o r U lt r a le n te wi t h a re d uc t io n i n t h e i nc id e nce o f h yp og l yc em ia . 67
H o we ve r , t h e c os t o f i nsu l in gl a r gi ne , i t s a va il a bil i t y on fo r mu l a ri es , a n d it s in co mp a ti bi l it y wi t h
o t h e r i ns ul in s i n t h e sa me s yr in g e ma y c au se s om e c li n ic ia ns an d p a ti e nts t o us e N P H
p r e f er e nt i al l y.
D u r i ng t he in i ti al vi si t , A .H . n ee d s t o l ea r n h o w t o i n je ct he r in su li n (s ee Qu e st i on 9 ), ho w t o
t e s t h er bl o od g l uc os e (se e Ta b le 50 - 17 ) , h o w a nd wh e n t o t es t h e r u r in e f o r k e to n es , a n d h o w
t o r ec og n i ze a nd t re a t h yp o gl yc em i a ( se e Ta bl e 50 - 2 5 ). S he al so ne e ds to u n de r st a nd th e
i m po r t an ce of me al pl a nn i ng an d th e re la t io ns h ip b e t we e n c ar b oh yd r a te in t ak e a n d i ns ul i n
a c ti o n. I t is ve r y im p or t an t no t to o ve r wh e lm A. H . wi t h i n fo rm a ti o n o n t he fi r s t vi si t . O ne s h o u ld
b e pa r t ic ul a rl y se n si ti ve t o t he ps ych o lo gi c al i mpa c t o f t h is d i ag n os is o n A . H . , ad d re ss he r
m a jo r c o nc e rn s, an d p r ovi d e on l y th e i n fo r ma t io n t h a t is ab so l ut e l y e ss ent i a l b ef o re t he ne xt
vi s i t . B e t we e n vi si t s, s h e s ho u ld be as se ss ed an d p r o vi de d i n fo rm a ti o n o n a n as - ne ed e d b as is
b y p h on e . Ta b l e 5 0 -1 6 l is t s im p or t a nt a re as of pat i e nt ed uc a ti o n.
A r e as o na bl e fi rs t ap p roa c h i n A . H . i s t o p r o vid e a t o ta l d ai l y do se o f 2 4 un i ts o f N P H
( a p p ro xi m a t el y 0 . 5 U / kg ) d i vi de d i n to t wo do s es : 1 6 un i ts 3 0 m in u te s b e for e b re ak f as t a n d 8
u n i ts 3 0 m in u te s b e fo r e d i nn e r . A n a l te r n at i ve o pt i o n wo u l d b e t o g i ve a si n gl e d a il y d os e o f 2 4
u n i ts o f i n su li n g l ar g in e , e i t he r at be d ti me o r i n t he mo r n in g . I t s ho ul d b e no t e d t ha t s om e
p h ys ic ia ns us e m or e c o ns e r va ti ve do se s i ni t ia l l y to e va lu a te a p at i en t ' s s en s it i vi t y to in su li n .
F u r t he r mo r e, as th e g l uco s e co n ce n tr a ti o n r e tu r ns t o n or m al , g lu co s e t o xi c i t y wi l l r ec e de an d
t h e p a ti e nt ma y r e qu i re le ss in su l in .
Selecting an Insulin Product
I f t h e c l in i ci a n d e ci d es t o u se a n i n te r m ed i a te i n s u li n in i t ia l l y, i s t h e r e a p re f e r en c e
b e tw e e n N P H o r L e n te in s u l in ?
Table 50-16 Areas of Patient Education
Diabetes: Pathogenesis and the complications
Hyperglycemia: Signs and symptoms
Ketoacidosis: Signs and symptoms (see Table 50-26)
Hypoglycemia: Signs, symptoms, and treatment (see Table 50-25)
Exercise: Effect on blood glucose concentrations and insulin dose (see Table 50-23)
Diet: See text. Emphasis placed on carbohydrate counting because the carbohydrate is
responsible for 90% of the rise in blood glucose following a meal.
Insulins:
Injection technique
Types of insulin
Onset and peak actions
Storage
Stability (look for crystallization and precipitation)
Therapeutic Goals: A1C, blood glucose, cholesterol, triglycerides, blood pressure
Self-Monitored Blood Glucose Testing: See Table 50-17
Interpretation of self-monitored blood glucose testing results
Foot Care: Inspect feet daily; wear well-fitted shoes; avoid self-care of ingrown toenails,
corns, or athlete's foot; see a podiatrist
Sick Day Management: See Table 50-24
Cardiovascular Risk Factors: Tobacco use, high blood pressure, obesity, elevated
cholesterol
Importance of annual ophthalmologic examinations; tests for microalbuminuria
Mo s t c l in ic ia ns us e N P H a n d L e nt e i ns u li ns in t er ch a n ge ab l y. Th e o ns e t o f a c ti o n, pe ak e ff ec t ,
a n d d u ra t io n o f ac ti o n o f t h es e t wo i ns u li ns a re ba s ic al l y th e s am e , a lt h oug h Le n te m a y h a ve a
s l ig h tl y sl o we r o ns et an d s li g ht l y lo n ge r du r at i on t h a n N P H . S om e h a ve s up p o r te d t h e us e o f
L e n te in su li n b e ca us e i t d o es no t c o nt ai n pr o ta min e , a p ro t ei n t h at is ra r e ly a n t ig e ni c.
H o we ve r , a l le r gi c r e ac t ion s to bo t h p r ot am i ne an d zi n c ( c on t ai ne d i n L e nt e i ns u li ns ) ha ve be en
r a r e .6 8
Th e r a pi d on se t o f re g ula r in s ul in is m o re li ke l y to b e r e ta i ne d wh e n mi xe d wi t h N P H th a n wi t h
L e n te in su li n , b u t l is pr o a n d a sp a r t ma y b e m i xe d wi t h ei t he r (s e e Q u es t io n 14 ) . Be ca us e A. H .
e ve n t ua ll y wi l l us e a m i xt u r e o f re g ul a r o r ra pi d - ac t in g i ns u li n a nd in t e rm ed i a te - ac t in g i ns ul i n,
N P H i n su li n c an be us ed i n it i al l y.
A l t h ou gh pu r i fi e d p or k i ns u li n i s s ti ll a vai l ab le , i t i s ra r el y u se d a n d p at i ent s s h ou ld be in i ti a te d
wi t h h um a n i ns ul i n. P o rk i ns u li n i s sl i gh t l y m o re a n t ig en ic a nd m o re e xp e n s i ve t ha n h u ma n
i n su li n .
Selecting an Insulin Syringe
W h a t k i n d o f i n s ul i n s yr i n g e s h o ul d be p re s c r ib e d fo r A. H . ?
I n su l in s yr i n ge s a r e pl a st i c , di s po sa bl e s yr i ng es wi t h n e ed l es t h at a re ve ry f i n e ( 2 8 t o 3 0
g a u ge ) , s ha r p , a nd we l l lu b r ic a te d t o e as e i ns e r tio n . Ne e dl es an d s yr i ng es ha ve b ee n i mp r o ved
s o th a t i ns ul in in j ec ti o ns a r e re la t i ve l y p ai n le ss i f p r o pe r te ch ni q ue is us ed . Le ss pa in is
a ss o ci at e d wi t h t he sm all e r , 2 9 - o r 3 0 - ga ug e ne ed l es . Th e “ d ea d s pa ce ” (a i r s p ac e a t t h e h ub
o f t he ne ed l e ) h as b e en vi r t u al l y el im i na t ed s o tha t mi xi n g an d m ea s ur i ng p r o bl em s p re vi o us l y
a ss o ci at e d wi t h i ts p r es en c e a r e n o l on ge r a c on ce r n . Th e l en g th s o f n ee dl e s a r e 5 / 1 6 , 3 / 8 , o r
1 / 2 i n ch . Th e sh o r te s t n ee d le ca n b e u se d fo r c hi ld r e n o r p a ti e nt s wi t h l it t le S C f at . 62
Ma n u f a c tu r e rs p ro d uc e 1 - , 0 .5 - , a n d 0 . 3 - mL s yri ng e s f o r U - 1 00 in su l in . F or p a ti e nt s su c h as
A . H . , us in g < 4 0 u ni ts o f in s ul in pe r in j ec ti o n, th e 0 . 5 -m L (l o w- d os e ) s yr i nge is p re f e rr e d.
S yr i n g es wi t h 0 . 3 -m L cap a ci t ie s a r e r ec om me n de d fo r pe d ia t ri c a nd pa t ie n ts us in g <2 5 u ni t s o f
i n su li n p e r i n je ct i on . Th e d os e m a rk in gs on t he 0.3 - m L a nd 0. 5 -m L s yr i ng e a r e m uc h e as ie r to
r e a d t h an th e 1 mL s yr i ng e , a l lo wi n g th e p a ti e nt to me as u r e i ns ul in mo r e e a si l y. In su li n
s yr i n ge s a r e a va il ab l e i n 1 - u ni t i nc r em en t s o r ½ -u n i t i nc r em en ts ( B D Ul t ra - F in e II S ho r t Ne e dl e
S yr i n g e, 1 /3 m L o n l y) . 6 2
A 0 . 5 m L U - 1 00 i n su li n syr i n g e wi t h a ½ in ch , 2 8 - o r 29 - ga u ge ne e dl e s hou l d b e p r es c ri be d f o r
A . H . C os t an d p a ti en t pre f e r en ce wi l l g o ve rn t he b r a nd se le c te d . S u bj ec t ive l y, p a ti en t s ca n
“ f e el ” t he di f fe r en ce b etwe e n d i ff e r en t b r a nd s, or t h e y m a y p re f er t he “ eas e o f bu bb l e r em o va l, ”
p h ys ic al c h a ra ct e r is ti cs , o r p ack a gi n g o f o ne s yr in g e o ve r an o th e r .
I n su l in pe n a n d d os in g de vi c es (e . g ., In n ol e t ) a re a ls o a va i la bl e fo r i n je ct in g in su li n . Th es e
d e vi ce s a r e us e fu l i n p a ti e n ts wi t h vis ua l o r de xt e r i t y p r ob le ms in wh o m u se o f a vi al an d
s yr i n ge m e th o d is di f fi c ul t . Pe ns r em o v e t h e n eed t o wi t hd r a w i ns ul i n, and t he in su l in do se is
d i al e d u p o n t h e d e vic e. P e n ne ed l es ar e a va i la ble i n 2 9, 30 , an d 3 1 g au ge a nd 3⁄ 1 6 , 5⁄ 1 6 , o r ½
i n ch le ng t hs . 62 , 69
Measuring and Injecting Insulin
H ow s h o ul d A. H . b e i n st r u c t e d t o m e as u r e a n d i n j ec t he r N P H in s u li n?
P . 5 0 -2 5
Agitation
A l l i ns u li ns , wi t h t h e e xc e p t io n o f re g ul a r, li sp r o , a s pa r t , a nd gl a rg i ne in sul i ns , a r e
s us p en si o ns a n d mu s t be a gi t at e d b ef o r e t he y a re wi t h d r a wn f ro m t h e vi al . A n e w, u n us ed vi al
o f N P H o r L en t e i ns ul in m a y r eq u ir e vig o r ou s a git a t io n t o l o os en t he s e dim e nt , wh i ch m a y ha ve
b e co me pa ck ed do wn wi t h s to r ag e . Th e vi al sh o uld b e r o ll ed be t we e n th e p a lm s o f t h e h an ds
t o mi ni mi ze f oa mi ng .
Measurement
F i r st , A . H. sh o ul d m ak e s u r e h er h an ds an d t h e in j ec t io n s it e a r e c le a n ( i t i s n o t n ec ess a r y t o
u s e a lc oh o l t o cl e an th e s i te ) . Sh e s ho u ld wi t h d raw t h e p lu n ge r to t he le vel o f i ns ul i n sh e
i n t en ds to in j ec t ( 1 6 u ni ts ) ; th en sh e s ho u ld in se rt t h e n ee dl e i n to t he vi al a n d i nj ec t 1 6 u n it s
o f ai r to p re ve n t c re a ti o n o f a va cu um wi t h in t he vi a l . Th e vi al th e n sh o ul d b e i n ve r t ed wi t h th e
s yr i n ge in se r t ed , a n d 1 6 u n i ts o f N P H s ho u ld be wi t h d r a wn . Th e be ve l o f t h e n e ed l e sh o ul d b e
we l l b el o w t h e s u rf ac e o f t h e i ns ul i n t o a vo id wi t hd r a wi n g a i r o r bu b bl es i nt o t he s yr i ng e .
Th e b a r re l o f th e s yr i ng e s ho u ld be he l d a t e ye l eve l t o c he ck fo r a i r b u bb le s a n d t o a ll o w
a cc u r at e p l ac em en t o f the p lu ng e r ti p a t t h e 1 6 -un i t m a rk . I f b u bb l es a r e p r e se n t, th e y sh o ul d
b e r em o ved b y ta pp i ng th e s yr i n ge ge n tl y t o c oax t h e b u bb l es to th e to p o f t he ba r r el , wh e r e
t h e y ca n b e i nj ec t e d b ack in t o t h e i ns ul in vi al . To r e mo ve ai r bu b bl es i n an i ns ul in pe n , p r im e
t h e n e ed l e wi t h 2 -u ni t s of i ns ul i n b ef o r e e ac h us e. A ls o , r e mo ve th e n e ed le f r om th e p en
d e vi ce in be t we e n u se s to p r e ven t a i r b ub b le s f r om ac cu mu la t in g .
Injection
A . H . n o w sh o ul d p r ep a r e a n a r e a f o r i nj ec t io n . A lc o ho l s wa b s m a y b e u s ed t o c le an t he ru b be r
s t op p e r o f t h e in s ul in vi al . To in j ec t t h e i ns ul in sub c ut a ne o us l y, A . H . s h ou ld b e i ns t ru ct e d t o
f i r ml y p in ch up th e a r e a t o be in j ec te d (t h is c r ea te s a f ir m s u rf ac e f o r th e i n je c ti on ) an d t o
q u ic kl y i ns e rt th e ne ed l e p e r pe nd ic u la r l y (9 0 - de gr e e an gl e ) i n to th e c en t er o f th is ar e a. Th e
s yr i n ge s h ou ld b e h el d to wa r d t h e mi d dl e o r ba ck o f t he ba r r el , l ik e a pen c il . An xi o u s p a ti e nt s
h a ve a t en d en c y to “c h ok e ” t h e h ub o f t he s yr i n ge , an d th is pr e v e n ts p r ope r n ee dl e i ns e r ti o n. A
4 5 - de g r ee an gl e o f in je ct i o n ma y b e u se d f o r i n fan t s a nd t hi n i nd i vi du al s wh o h a ve li t tl e S C f a t.
Th e s ki n p in ch sh o ul d b e r e le a se d a nd t he in su li n i n je ct e d. 6 9 P r es su r e s ho u ld be a pp li e d a t
t h e s i te of in je c ti o n f o r 5 t o 8 se co n ds to pr e ve n t b a ck l e ak ag e o f th e i ns ul i n a s t he ne e dl e i s
r e m o ved . Th e s it e s ho u ld n ot be ma ss ag e d, be ca u se th is ma y ac c el e ra t e t h e a bs o rp t io n a n d
o n se t o f ac ti o n o f i ns ul i n ( s ee Ta b le 50 - 12 ) . W hen us i ng an in su li n pe n , th e ne e dl e s ho ul d b e
e m be d de d wi t hi n t h e sk in f o r a bo u t 5 s ec o nd s a ft e r de p re ss i ng th e p l un ge r t o e ns u re fu l l
d e li ve r y o f t h e i ns ul i n d os e .
P a t i en ts wh o a re an xi o u s ab o ut se l f - i nj ec t io n c an b e h el p ed b y a p pl yi ng a n ic e cu b e t o t h e si t e
b e f o re in je c ti on o r b y us in g an in je c ti on ai d . Ho we ve r , in j ec ti o n a id s a re ge n e ra l l y u n ne ce ss a r y
o n ce th e p a ti e nt r ea l i zes t h a t in j ec ti o ns ar e re l at ive l y p a in f re e wi t h p r op er t ec h ni q ue .
Rotating Injection Sites
P r e vi o us l y, p a ti e nt s we r e a d vis ed to r o ta t e i nj ec ti o n s it es be t we e n th e a rm s , t hi g hs , a bd om e n,
a n d b u tt oc ks ( Fi g . 5 0 -6 ) . H o we ve r , d i ff e r en ce s i n t h e ra t e o f i ns ul i n a bs o rp t i on f ro m t he se si t es
r e s ul t ed in al t er e d g lu cos e c on t r ol . 70 N o w, t he AD A r e co mm en ds t ha t i nsu l in in j ec ti o ns b e
r o t a te d wi t hi n t h e s a m e a n a to mi c r e gi on t o a vo id t h is ef f ec t . 6 9 , 7 1 So me re c omm e nd in su l in
i n je c ti on s i n to th e a b dom i na l a r ea be ca us e ab sor p t io n f ro m t hi s si t e i s l ea s t a f fe c te d b y
e xe r c i s e a nd th e m os t p re d ic t ab le . A lt e rn a ti ve l y, A . H . ca n b e i ns t r uc te d to r o t at e h e r m o rn in g
i n je c ti on wi t h in on e re g io n ( e. g ., t he th i gh ) a n d he r e ve ni ng in j ec ti o n i n an o t he r an a to mi c
r e g io n . T hi s m in im i zes th e va r ia bl es t ha t c an al te r h er r es po ns e to in su lin .
FIGURE 50-6 Selecting insulin injection sites. (Used with
permission from reference 300.)
View Figure
R o t a ti n g i nj ec t io n s it es al s o wa s r ec om me n de d a t o n e t im e t o a vo i d t he li po d ys t ro p hi c e f fe ct of
i n su li n (l i po h ype r t r op h y a n d l ip o at r o ph y) ; ho we ve r , be ca us e i ns u li n h as b e e n p ur i fi e d, t he se
c om p li ca t io ns a re le ss fre q u en t a n d t he im po r t anc e o f ro t a ti on is le ss c r it ic a l. N e ve r th el es s ,
r e p e ti ti ve us e o f th e s ame si t e o f i nj e ct io n m a y s ti l l r es u lt in li p oh yp e r tr o ph y a n d i t d oe s
t o u gh e n t he s ki n , m ak ing n ee dl e pe ne t r at i on m or e di f f ic ul t . F u r th e rm o re , i ns u li n a bs o rp t io n
f r o m l ip oh yp e r t ro p hi c si te s c an b e sl o we d . 72
Self-Monitored Blood Glucose
S h o u l d A. H . s e l f -m o ni to r h e r bl o o d g lu c os e ? W h a t t yp e s o f h om e bl oo d g lu c os e
m o n i to r i n g t e s ts a re a va i l a bl e , a n d w h a t a r e the m aj o r di f f e r en c es be tw e en t he m ? H ow
a c c u ra t e a r e r es u l ts obt a i n ed f r om h om e b l o od g l uc o se t es t i ng ?
Th e a d ve nt o f S MB G r e v o l u ti on i ze d t he ma n ag eme n t o f di ab e te s m el li t us b y p r o vi di ng a s im pl e
a n d p o r ta bl e m e th od f o r p e r io d ic a n d r e pe a te d me a su r em e nt of bl o od gl uc os e i n th e
a m bu l at o r y c a r e se t ti n g. B a s ed on th e re su l ts of th e D C C T, t h e A D A r ec om me n ds th a t mo s t
i n di vi d ua ls wi t h di ab e te s s ho u ld at t em p t t o a t ta in a n d ac h ie ve no r mo g l yc em i a as sa f el y as
p o ss ib l e. Fo r pa t ie n ts wi t h t yp e 1 d i ab e te s, t hi s ca n
P . 5 0 -2 6
b e ac hi e ve d o nl y b y us ing S MB G ; t h e r e fo r e , a ll t re a tm e nt p ro g r ams s h ou ld i nc lu de t he r ou t in e
u s e o f d ai l y gl uc os e m o ni t o ri n g. A l th ou g h t he e xa c t f re qu e nc y a nd ti mi n g o f bl o od gl uc os e
t e s ts s ho u ld be di ct a te d b y i n di vi du a li ze d p a ti e nt g o al s , mo s t p at i en ts wi t h t yp e 1 d ia be t es
s h ou l d p er f o rm S MB G t h r e e or mo r e t im es da il y. 42 , 7 3 S MB G i s e sp ec ia l l y i m po r t an t i n (1 )
p r e gn a nc y co mp l ic at e d by d i a be t es , ( 2 ) p a ti e nt s wi t h u ns t a bl e d ia b et es , (3 ) p at i en ts wi t h a
p r o pe ns i t y to se ve r e k eto s is o r h ypo g l yc em i a, ( 4) p a ti e nt s p r on e t o h yp og l yc em ia wh o ma y n ot
e xp e r i e nc e th e u su a l wa r n i ng s ym p to ms , a n d ( 5 ) p a t ie n ts o n i n te ns i ve i nsu l in r eg im e ns .
G l u c os e mo n it o ri n g s ho ul d al so be pe r f or me d m or e f r eq ue n tl y wh e n e ve r th e r ap y i s mo d if i ed .
B e c au se A . H . is be i ng ini t i at e d o n i ns ul in t he r ap y wi t h t h e g oa l o f n o rm o glyc e mi a , s he s h ou l d
s e lf - mo n it o r h e r b lo o d g lu c os e a m in im um o f t h ree t im es pe r d a y.
S e l f -m on i to r i ng of bl o od g l uc os e h as be e n wi d e l y a cc ep t e d b y bo t h p at i ent s an d c li ni ci a ns .
B e c au se bl o od gl uc os e te s ti n g ma t e ri a ls c on s ti t ut e a m ul ti mi l li on do l la r bu s in es s, t he m a rk e t
h a s b ee n f l oo d ed wi t h a m u lt i tu d e o f m et e rs , a n d t h e te ch no l og y i n t hi s a re a is c ha n gi n g
r a p id l y. N e w mo n it o rs a re i nt r o du ce d yea r l y. 73
A l l m o ni to r s u se s t r ip s an d a re s e lf - t im in g , r eq u i ri n g n o p a ti en t ac ti o n a f ter t h e b lo o d is pl ac e d
o n th e s t ri p . Se ve r al fa c to r s s ho u ld be ta ke n i n to a cc o un t wh e n e va l ua ti n g a mo ni t o r a nd it s
a p p ro p r ia t en es s f o r a n in d i vid u al . Th e p r im a r y co n si d er a ti o ns a r e e as e of u se , a cc u ra c y
r e l at i ve to a r e fe r en c e sta n d ar d , r e li a bi li t y, in su ra n ce c o ve r ag e a n d co s t. 6 2 , 74 C on ve n ie nc e
f a c to r s in cl u de me t er si ze , vo lu me o f b lo od r eq u ire d fo r te s ti ng , s i te t o o bta i n s am pl e (e . g. ,
f i n ge r ve rs us al t e rn a te s it e su ch as fo r ea r m ), c a pa c it y o f t h e m et e r t o s to re b lo od gl u co se
va l u es (m em o r y) an d m an a g e d at a , t es t in g t im e , s i ze o f re a d -o u t, ge n e ra l a va i la bi l it y o f s t ri ps ,
a b il i t y to tu r n o f f a u di bl e s ig n al s, an d a va i la b il it y o f t ec hn ic al su pp o r t . S om e d e vic e s a re le ss
r e l ia b le fo r us e i n a ne mic pa t ie n ts (e . g ., r en a l t r an s pl a nt pa t ie n ts ) , a nd al l f u nc t io n m os t
r e l ia b l y wi t hi n c e rt a in tem p e ra t u r e ra n ge s ( us u all y 6 0 ° t o 9 5 ° F ) a nd hu mid i t y ( ge n er a ll y < 90 % )
c o nd i ti on s . S t r ip s a r e sen s it i ve to li gh t , m oi st u r e, a n d t em pe r a tu r e e xt r e me s a n d mu s t b e
s t o re d a n d h an dl e d wi t h c a r e.
S e ve r a l g en e ri c s t ri ps have b ec o me a vai la b le ( Q ui ck C h eck , Bi o te l ) , o f fe r i n g pa t ie n ts a n
i n e xp e n si ve s o lu t io n t o th e c os t of f re q ue n t mo n ito r i ng if t he i r i ns u ra nc e do e s n ot co ve r th em .
Th e s e s t ri p s a re ad ve r t ise d as b e in g c om pa t ib l e wi t h s e ve ra l m e te r s. H owe ve r , f e w s t u di es
c o nf i rm i ng th e ir eq u i val en c y t o b r an d n am e s t ri ps e xi s t . O n e s tu d y fo u nd th a t b r a nd na me
s t r ip s, wh i c h a re ca li b r ate d to t he m ac h in e b y t he m an u fa c tu r e r, we r e mo re ac cu r a te an d
p r e ci se th a n t he ge n e ri c s t r ip s. 7 5 ( N o te : Ac cu r acy i s a me as u r e o f a g re em e nt wi t h a s ta nd a r d
r e f e re nc e , a n d p re ci si o n i s a me as u re o f va r ia t io n b e t we e n r e pe a te d t e st s.) I f A . H. wa n t s t o t r y
g e n er ic st r ip s , sh e s h ou ld co mp a r e h e r r es ul t s wi t h a l ab o r at o r y de t e rm ina t i on to en su r e t h a t
t h e s t ri ps a re p ro vi d in g a cc u r at e re su l ts . Ca p il lar y va l u es me as u re d b y th e gl uc os e m e te r a r e
l i ke l y to be 10 % to 15 % lo we r t h a n va l ue s m ea su re d b y th e l ab o r at o r y un le ss t he m e te r ha s
a l r ea d y be e n c al ib r a te d to p la sm a l e vel s. S he al so co u ld c om p a re r es ul ts o b t ai ne d f ro m t he
g e n er ic st r ip s wi t h t ho s e o f th e b r an d n a me s t r ips .
P a t i en t e d uc at i on r eg a rdi n g t es t in g p r oc e du r es , th e im po r t an ce of r ec o rd in g r es ul ts , a n d t e s t
t i me s a r e c ri t ic al . Ul t im at e l y, A . H. sh o ul d b e t a ugh t ho w t o us e b l oo d g l uco s e va l ue s t o a dj u st
h e r i n su li n d os e , d ie t a r y i n t ak e, an d e xe r c i se pa t te r n ( Ta bl e 5 0 - 17 ) .
U s e d p r op e rl y, a va il ab l e m e te r s p r o vid e a cc u ra t e, p r ec is e re su l ts th a t ca n b e us ed b y pa ti e n ts
t o ma na g e t he i r d i ab e te s ( s ee Ta b le 50 - 17 ) . H o we ve r , se ve r al fa c to r s ca n a f f ec t t he ac cu r ac y
o f me t er r es ul t s — mo s t co mm o nl y, eq u ip me n t m alf u nc t io n a n d h um an e r ror . P r o bl em s wi t h a
m e te r c a n b e d e te ct e d by p e r f o rm in g a qu al i t y - con t r ol t es t o nc e we ek l y and wi t h ea c h n e w vi a l
o f st r ip s ; h um an e rr o r c an b e mi n im i zed wi t h a d eq u a te t ra i ni ng . Ta bl e 5 0 -1 8 li st s f ac t o rs th a t
c a n a f fe ct r es ul ts o f S MB G t e s t r es ul t s. A n yti me S MB G va l u e s a r e in c on si s te n t wi t h t he
p a t ie n t 's s ym p to ms o r A 1 C va l u es , s ou r ce s o f e r r or s ho u ld be e val ua t ed ( se e Ta b le 50 - 6 ).
A . H . ' s te ch n iq ue
P . 5 0 -2 7
s h ou l d b e r e vie we d p e rio d ic al l y, be ca us e c li n ic al d ec is io ns a re ba se d o n t h e p a ti en t ' s b lo o d
g l uc os e t e st in g re co r d .
Table 50-17 Self-Monitored Blood Glucose (SMBG) Testing: Areas of Patient Education
When and How Often to Test
Technique
How and when to calibrate the glucose monitor.
Review all “buttons” and their purposes. Identify battery case. Review cleaning procedures.
Preparation
1.
2.
3.
4.
Calibrate monitor/set code for batch of test strips.
Turn machine on.
Prepare all materials: tissue, strip, lancet.
Remember to close the lid of the strip container immediately. Strips exposed to air
and moisture deteriorate rapidly.
5. Wash hands with warm water. Dry thoroughly. A wet finger causes blood to spread
rather than form a drop. Milk the finger from the base to ensure an adequate flow of
blood.
6. Lance the tip of the finger. Avoid the pads of the finger where nerves are
concentrated.
7. Hold the finger below the heart with the lanced area pointing toward the floor.
8. Once a sufficient amount of blood is available, quickly apply blood to designated
area of the test strip. Depending on the strip type, the blood sample is placed in an
area on the surface of the strip or it is applied to the side of the strip where it is taken
up by capillary action.
Record Results in a Log Book and Bring to All Clinician Visits. Include Relevant
Information Regarding Diet or Exercise
How to Use Results to Achieve Normoglycemia
Table 50-18 Factors That Can Alter Self-Monitored Blood Glucose Test Results:
Troubleshooting
Glucose monitor not coded for batch of test stripsa
An inadequate amount of blood applied to test stripb
Dirty glucose monitora
Low batterya
Test performed outside of temperature and humidity operating conditionsa
Lowc or highb hematocrit
Dehydrationb
Hyperosmolar, nonketotic stateb
Lipemiaa
High levels of ascorbic acid or salicylates (rare)b
a
Effect unpredictable.
Values tend to be lower.
c
Values tend to be higher.
b
Testing Frequency
H ow of t e n a n d w h e n s ho u l d A. H . b e i ns t r u c te d t o t es t he r b lo o d g l uc os e co n ce n t r a ti o ns ?
Th e o b je ct i ve o f on go i ng, f r eq u en t b l oo d g l uc os e t e s ti ng is to de t e rm in e wh e t he r
n o r mo gl yc em ia is be in g a c hi e ve d a nd to as se ss th e ac ti o n o f s pe ci f ic i ns ul i n d os es as we l l a s
t h e i mp ac t of m e al s , f ood , il l ne ss , o r e xe r c i se on b l oo d g lu c os e l e vel s. Ide a ll y, p at i en ts sh ou l d
t e s t t he i r b lo o d g lu co se c o nc en t r at i on be f o re m ea l s, 90 t o 1 20 m i nu t es a ft e r m e al s t o
d e t e rm in e t h ei r “i ns u li n to ca r b oh yd r a te ra t io , ” a t b e d ti me , a n d oc c as io na l ly, a t 2 o r 3 A M ( i . e . ,
e i gh t ti me s d ai l y) . Ho we ve r , mo s t p at i en ts a re una b le t o a dh e re t o su ch a r i go r o us re g im en . At
t h e m in im um , to de t e rm in e he r da il y i ns ul i n r e qu ir e m en ts , A . H. sh ou l d t est h e r b lo o d g lu co se
c o nc en t r at i on s si x t o e i gh t ti m es d a il y: be f o re and a f te r e ac h m e al an d a t b e dt im e . S h e a ls o
s h ou l d se t h e r a l ar m f o r 3 A M t wo o r t h r e e t im es p e r we e k a nd te s t h e r b lo o d g lu c os e a t t h at
t i me . Bl o od gl uc os e c onc e nt r a ti o ns m ea su r e d a t t h es e ti me s mo r e o r le ss c o r re sp o nd to th e
p e ak ac ti o n o f s ho r t - a nd i n te r me di a t e - ac t in g i ns ul i ns ad mi ni s te r ed a t va r io u s t im es of t he da y,
e n a bl in g t h e cl i ni ci a n t o e va l u at e t h e e f fe ct o f var i o us i n su li n c om po n en t s o n m ea ls an d to
i d en t i f y n oc t u rn a l h yp og lyc e mi a . F o r e xa m p l e, the b lo od gl u co se m e as u red b ef o r e d in ne r
r e f le c ts th e a ct i on of A . H. ' s mo r ni n g d os e o f N P H o n fo o d sh e h a s e at e n f or b r ea k f a st an d
l u nc h , as we l l a s h e pa t ic g l uc os e p r od uc t io n b e t we e n m ea ls . In c re as in g l y, p a ti e nt s wh o u se
c a r bo h yd ra t e c ou n ti ng wi t h ra pi d - ac ti n g i ns ul in s a r e be in g a d vis e d t o t es t 2 - h ou r p o st p ra n di al
l e ve ls on in i ti a ti ng t he r ap y t o en ha n ce pr o pe r dos a ge ad j us tm e n t . ( Ta bl e 5 0 - 19 )
Th e i mp o r ta nc e o f f re que n t b l oo d g lu c os e t es ti ng ca n no t b e o ve r em p ha si ze d . W hen bl o od
g l uc os e i s t es t ed le ss fre q u en tl y t h an fo u r tim e s d a il y, g lu co se c o nt r o l d et e r io r a te s t o b as e li ne
l e ve ls . Th is i s b ec a us e co m pl e te p ro f il es ar e n o lo n g er a vai l ab le , an d i t i s i mp os si b le to ad j us t
i n su li n d os e s b as ed on ra n d om b l oo d g lu co se con c en t r at i on s. 7 6 I f p a ti e nt s re f us e t o te st f ou r
t i me s d ai l y, th e y sh ou l d b e en co u ra g ed t o t es t f ou r t im es d a il y o n r e pr e sen t a ti ve da ys of t he
we e k o r to te s t a t d if f e ren t ti m es o f th e d a y ea ch d a y so t ha t a we e k l y p r of i l e ca n b e
d e ve l op ed . A . H. al so sho u ld be e nc ou r ag e d t o t es t he r b l oo d g l uc os e co nc e nt r a ti o n a n y tim e
s h e is f ee li n g u nu su a l o r t o e val ua t e t h e e ff e ct of u n us ua l c i rc ums t an c es o n he r bl oo d g l uc os e
c o nc en t r at i on ( e. g ., in c re a se d p h ysi ca l e xe r c i se , a la r g e h ol id a y me al , fi na l e xa m in a ti on s , a
f a mi l y cr is is ) .
Table 50-19 Interpreting Self-Monitored Blood Glucose Concentrationsa
Test Time
Target Insulin Dose
Target Meal/Snack
Prebreakfast
(fasting)
Predinner/bedtime intermediate- or
long-acting insulin
Bedtime snack
Prelunch
Prebreakfast regular insulin
Breakfast/midmorning
snack
Predinner
Prebreakfast intermediate-acting
insulin and/or prelunch regular
insulin
Lunch/midafternoon snack
Bedtime
Predinner regular insulin
Dinner
2-hour
postprandial
Premeal lispro insulin or insulin
aspart
Preceding meal or snack
3 AM or later
Predinner intermediate-acting
insulin
Dinner/bedtime snack
a
Considerations: (1) Assumes a normal meal pattern. For patients who travel, have odd
working or sleeping hours, or irregular meal patterns, these rules may not apply. (2)
Assumes administration of regular insulin 30 to 60 minutes before meals or lispro insulin 0
to 15 minutes before meals and a normal pattern of insulin response (see Table 50-12 for
factors that can alter insulin absorption and response). (3) If prebreakfast concentrations are
high, rule out reactive hyperglycemia (Somogyi reaction or posthypoglycemic
hyperglycemia). Consider contribution of dawn phenomenon as well. Whenever blood
glucose concentrations are high, consider reactive hyperglycemia (excessive insulin doses).
(4) Consider accuracy of reported test results: (a) Do they correlate with A1C and patient's
signs and symptoms? (b) What is the patient's compliance? Could results be fabricated? (c)
Is patient's technique appropriate? Check timing, adequate blood sample, machine, strips,
and calibration (see Table 50-18). (d) Are insulin kinetics altered? (see Table 50-12) (e)
Meals: consider content, quality, and regularity.
Noninvasive Blood Glucose Testing
Ma n y p a t i e nt s re f us e t o p e r f or m S MB G o r g ro w t i r e d of s e lf - t es ti n g b ec aus e o f th e d is co m fo r t
o f t he fi n ge rs t ic k. Th u s, m uc h re se a rc h i s b ei n g d o n e in t he a re a o f n o nin va s i ve b lo o d g lu co se
t e s ti ng . Th e G lu coW atch ( C yg n us I nc . , R e d wo o d C i t y, C a li f o rn ia ) is a no ni n va si ve , wa t ch l ik e
d e vi ce th a t u se s r e ve rs e i o nt o ph o re si s t o c ol l ec t g l uc os e s am pl es t hr o ug h i n ta c t sk in vi a
i n t er s ti t ia l f l ui d. Th e de vi c e a ll o ws us e rs to m o ni to r t he i r g lu co se le ve ls au t om a ti ca l l y, u p t o
t h r e e t im es p e r h o u r f o r 1 2 ho u rs . I t ha s a n a la rm f or lo w o r h ig h re a di ngs . Th e d e vic e i s
a va i la b le b y pr es c ri p ti o n o n l y a n d r es t r ic te d to ad u l ts 1 8 yea r s o f a g e o r o l de r o r ch i ld r en 7 t o
1 7 ye a rs o f ag e wi t h d iab e t es . Di sa d va nt a ge s i nc l ud e t h e n ec es si t y of dai l y ca l ib r at i on wi t h a
b l oo d g l uc os e m et e r , a lo n g wa r m -u p p e ri o d ( 3 ho u r s) an d a hi g h c os t f o r t h e m et e r a nd
s t r ip s. 7 7
Using Blood Glucose Test Results to Evaluate Insulin Doses
A. H . w a s i n s t r uc t ed t o in j e c t h e r se l f tw i c e d a ily w i t h N P H i n s ul i n : 1 6 u n i t s b e fo r e
b r e a k fa s t a n d 8 un i t s be f o r e d i n ne r . S he w a s as k e d t o te s t h e r bl o od g l u c os e e i gh t t im e s
d a i l y ( b e f o r e a n d a f t e r m e a ls an d at b ed t i me ) , t o r e co r d he r r e su l t s an d o t he r u nu s ua l
e ve n t s o r s ym p t o m s d ur i n g t he da y, a n d t o b rin g h e r r e c o rd s to t he cl i n i c. A. H . w a s a l s o
i n s t r uc t e d t o ke e p a foo d d ia r y a n d r e c o r d t h e n u m be r o f c a r bo h yd r a t e s sh e in g es t e d a t
e a c h m e a l . T h e i n i ti a l go a l o f t h e ra p y i s t o a c hi e ve p r e p ra n d ia l b l o od g l u c os e
c o n ce n t r a ti o ns o f < 1 80 m g / d L a nd t o e l im i na t e s ym p t o m s o f h yp e r g l yc e m i a. O n e w ee k
l a t e r , t r e n ds i n h e r b l oo d g lu c os e c o n ce n t r at io n s w e re a s f o ll ow s :
Time
Glucose Concentration (mg/dL)mmol/L
7 AM
160–200
8.8–11.1
Noon
220–260
2.2–14.4
5 PM
130–180
7.2–10.0
11 PM
140–180
7.8–10.0
O c c a s io n al 3 AM te s ts a ve r a g e d 1 60 mg / d L a nd A. H . ' s u r i ne is n eg a t ive f o r k e to n es . S he
e a t s b e tw ee n tw o a n d fo u r c a rb o h yd r a t e s e r vi n g s (3 0 to 60 g ) p e r m ea l . S ub j ec t i ve l y, A. H .
feels a bit
P . 5 0 -2 8
b e t t e r , a n d h e r w e i g ht h a s s t a bi l iz e d, b u t s he s t i l l u r i n at e s tw o t o t h re e t im e s n i gh t l y.
H ow w o ul d yo u i n t e r p r e t t h es e re s ul t s , a n d how s h o ul d A. H . ' s i n su l in d o se be al t e r ed ?
H e a l th c a r e p r o vid e rs s ho u ld us e t h e d at a o b t ai ne d f ro m s el f -m on i to r in g to ( 1 ) s et gl yc em ic
g o al s , ( 2 ) d e vel o p r ec omm e nd a ti o ns f o r p h a rm aco l og ic t he r ap y, ( 3 ) e va lua t e th e e f fe c ti ve ne ss
o f ph a rm ac o lo gi c t h e ra py, ( 4 ) in st r uc t pa t ie n ts to i n te r p re t an d r e sp on d to b l oo d g lu c os e
p a t te r ns , (5 ) e val u at e t he im p ac t o f d i et a r y fa c tor s on gl yc em ic c o nt r ol , (6 ) mo d if y t he r a p y
d u r in g a cu t e /i n te rc u r r en t i ll n es s o r wh e ne ve r pa t ie n ts r ec ei ve me di ca t io ns k no wn t o af f ec t
g l yc em ic c o nt r ol , (7 ) m od i f y t he m a na ge m en t p lan i n r es p on se to a c ha nge i n ac t i vi t y l e ve ls ,
a n d (8 ) i d en t if y h yp o gl yce m ic u n a wa r e ne ss . 4 2
B e f o re us i ng A . H. ' s b l ood g lu co se r es ul ts t o a dj us t he r i ns u li n d os e , i t i s im p o rt a nt to ob s er ve
a n d re as se ss he r te st i ng t e ch ni q ue . O ne al so sh ou l d d e te r mi ne wh e t h er t he r e we r e an y
u n us u al c i rc um st a nc es in h e r li f e , d ie t , o r e xe r c is e p a t te r ns o ver t he pa st we e k t ha t m ig h t h a ve
a f f ec t ed he r re sp o ns e t o i ns u li n . O n ce th es e h a ve b ee n ru le d o u t a s co n fo u n di ng f ac to r s, on e
c a n b eg i n ma ki n g g r oss a d ju s tm en ts in A . H . 's in su l in do se , r ea li zi n g t ha t fi n e -t u ni n g wi l l be
i m po ss ib l e u nt il a c on si st e n t d ie t an d e xe r c i se pat t e r n h a ve b ee n i ns t i tu t ed .
S e ve r a l p r in ci pl es mu st b e k e pt in mi nd wh e n e ver b lo o d g lu co se t es ts a r e u se d to ad ju s t a
p a t ie n t 's ba si c i ns ul i n d os e ( Ta bl e 5 0 -2 0 ) . B ec a us e m an y f ac t o rs c a n a lt er a pa t ie n t 's r es po ns e
t o in su l in , i t i s i mp o rt a nt t o us e b lo od gl uc o se c on c en t r at i on t re nd s m ea su r e d o ve r a mi ni mu m
o f 3 d a ys t o a dj us t th e ba s ic i ns u li n d os e (i . e. , the d os e t he pa t ie n t wi ll us e e ve r y d a y) . T h e
o n l y e xc e p ti on to t hi s r u le is t he us e o f s up pl em en t a l i ns ul in do se s t o c o r re c t e xc e p t io n al l y
h i gh gl uc o se c o nc en t r at io n s a f te r A . H. ha s a cq ui re d s o ph is t ic at e d i ns ul i n a d ju s tm en t s ki ll s
( s e e Q u es t io ns 17 an d 18 ) . S MB G r e s ul t s sh o ul d b e e va l ua t ed in c o nj u nct i o n wi t h o th e r
p a r am e te r s su ch as A 1 C a n d p e ri o di c l ab o ra t o r y bl o od gl uc o se m e as u re men t s .
Th e t wi c e - da i l y d os e o f N P H i s i na d eq u at e l y c ont r o ll i ng A . H . 's s ym p to ms a n d b lo o d g lu co se
c o nc en t r at i on s. S he is ac h ie vi n g so me r es po ns e i n th e l a te af t e rn o on , b u t t h e d el a ye d o ns e t o f
N P H a c ti o n a nd in ad e qua t e to t al da il y d os e h a ve r e su l te d i n p o or co n t ro l o f he r bl o od gl uc os e
c o nc en t r at i on s o ve r al l . Th e bl oo d gl uc os e c on ce nt r a t io n o f 1 6 0 mg / dL a t 3 A M i n d i ca t es th a t
r e b ou n d h yp e rg l yce mi a is an un l ik el y ca u se of her h ig h fa st i ng le ve ls (s e e Q u e st i on s 1 5 a nd
1 8 ) . As a n i n it i al s t ep towa r d c o nt r o l, A . H . 's e ven i ng do s e o f N P H co u ld b e in c re as ed in an
a t t em p t t o c on t ro l h e r f as t in g h yp e r gl yc em ia . H owe ve r , t h i s a pp r oa ch doe s n o t a dd r es s A. H . ' s
e l e va te d p r el u nc h va l ue s.
Th u s , if A . H . is c a pa b le a n d re ad y t o l e ar n ho w t o mi x s h o r t -a c ti ng an d i nt e r me d ia t e - ac t in g
i n su li ns , th e s pl i t -m i x a pp r o ac h i s p r ef e r re d :

I n c re as e th e t o ta l d a il y do s e o f i ns ul i n sl i gh t l y b ec a us e h e r o ve r al l c on t ro l i s p oo r , a n d
h yp e r gl yc em i a in c re as e s r e si st a nc e t o i ns u li n a cti o n ( e . g. , 0 . 6 U/ kg × 5 0 k g = 3 0 u ni ts ) .

S p l it t he do se of in s ul in s o th a t a pp r o xi m a te l y t wo - t hi r ds ( 21 un i ts ) i s a dm i ni st e r ed i n
t h e m o rn i ng an d o ne - t hi rd ( 9 u n it s ) is ad mi n is te r ed i n t he e ven i ng .

P r o vi d e a 2: 1 ra t io of N PH : r e g ul a r o r i ns u li n l is p ro o r a sp a r t i n t he mo r ni ng ( 1 4 U / 7 U )
a n d e ve n in g ( 6 U /3 U ) .
Table 50-20 Factors That Can Alter Blood Glucose Control
Diet
Insufficient calories (e.g., alcoholism, eating disorders, anorexia, nausea, and vomiting)
Overeating (e.g., during the holidays)
Irregularly spaced skipped or delayed meals
Dietary content (e.g., fiber, carbohydrate content)
Physical Activity
See Table 50-23 and Question 30
Stress
Infection
Surgery/trauma
Psychological
Drugs
See Tables 50-36 and 50-37 for information about medications that affect blood glucose
levels
Hormonal Changes
Menstruation: glucose concentrations may increase premenstrually and return to normal
postmenses
Pregnancy
Puberty: hyperglycemia probably related to high growth hormone levels
Gastroparesis
Delays gastric emptying time. Peak insulin action and meal-related glucose excursions may
become mismatched
Altered Insulin Pharmacokinetics
See Table 50-12
Insulin Injection Technique
Measuring
Timing
Technique
Inactive Insulin
Outdated insulin
Improperly stored insulin (heat or cold)
Crystallized insulin
I f t hi s a pp r oa c h is us ed , i t is e ss e nt i al th a t A . H . in c o rp o ra t e a be d ti me s na ck in t o h e r d ie t a n d
t e s t h er bl o od gl uc os e co n ce n t ra t io ns pe r io d ic al ly a t 3 A M t o en su r e t h at s h e d oe s n o t su f fe r
f r o m n oc t ur n al h ypo g l yce m ia .
Mixing Insulins
A. H . i s a n xi o us t o g e t he r d i ab e t es un d e r c o n t ro l a nd ag r e es t o m i x t he N P H a nd r e gu l a r
i n s u li n s. H ow sh o u ld sh e be i ns t r u c te d to mea s u r e a n d w i t h d raw t h is i n su l in m ix t u r e?
Th e p r oc e du r e u se d t o mi x a n d wi t h d r a w N P H a nd r e gu la r in su li n i s b as ica l l y th e s am e a s t ha t
d e sc r ib ed in Q u es ti o n 9 . Th e m aj o r d if f e re nc e i s t h a t a n a de q ua t e vo l um e o f ai r m us t b e
i n je c te d i n to th e N P H vial b ef o r e t he r eg ul a r o r ins u li n l is p ro o r as p a rt is m e as u re d a n d
wi t h d r a wn . A ls o , r e gu l ar i n su li n i s m ea su r ed an d wi t h d r a wn i n to th e i ns u lin s yr in g e f i rs t t o
a vo i d c on t am in a ti o n o f th e vi al of r eg u la r o r as pa r t o r li s pr o i ns u li n wi t h N P H . C o n ta mi n at i on
wi t h N P H u l ti ma t el y a lt e rs t he N P H : re g ul a r i ns ul in r a ti o t h at is ad mi ni s te re d . W hen pa t ie n ts
P . 5 0 -2 9
wi t h d r a w N P H o r Le n te in s ul in f ir s t, t he vi al of r eg u la r in su l in e ven t ua ll y b e co me s c lo ud y. I n
c o nt r as t , c on t am in a ti o n o f t he N P H i ns u li n wi t h re g ul a r i ns u li n p r ob a bl y is in si g ni f ic an t
b e ca us e th e p r ot am i ne co n t ai ne d i n N P H c an bi nd t he r eg u la r i ns u li n (s e e Q u es t io n 1 4 ) . Th e
p r o ce du r e A. H . s h ou l d us e to m i x h e r in su li ns is d e sc r ib ed in t he fo l lo wi ng se c ti on , us in g h e r
m o r ni ng do se as an e xa m p le .

A f t e r d is p e rs in g t h e N P H i ns u li n s us pe ns i on , i n jec t 14 un i ts o f ai r i n to th e N P H vi a l a nd
wi t h d r a w t h e n e ed l e.

I n j ec t 7 un i ts o f a i r i n to th e r eg ul a r i ns u li n vi a l, an d wi t h d ra w t h e 7 un i ts o f in su l in as
d e sc r ib ed in Q u es ti o n 9 .

I n se r t th e n e ed le in t o t he N P H vi al , an d p ul l th e p l un g e r d o wn t o t he 21 - un i t m a rk (1 4
u n i ts o f N P H p l us 7 un i ts o f re g ul a r i ns ul i n ).
Stability of Mixed Insulins
W i l l m i xi n g N P H w it h r eg u l a r i n s ul i n b l u nt t he r a p i d a c t io n of r e gu l a r i n s u li n ? How s t ab l e
a r e o th e r in s u li n m i x tur e s ? ( Se e Ta bl e 5 0 -2 1 . )
Regular Plus NPH
Th e o ns e t a nd du r a ti o n o f ac t io n o f re gu l a r a nd N P H i n su li n a dm i ni st e red as a m i xt u r e a r e
s im i la r to th os e o bs e r ved wh e n t he t wo in su l in s a r e ad mi ni s te r ed b y s e pa r a t e i nj ec ti o n . Th e
p h a rm ac o d yna mi c p ro f il es o f t he se in su l in s a r e r et a i ne d i n p r em i xe d p re p ar a t io n s st o r ed in
vi a l s o r s yr i ng es fo r 3 mo n t hs . 7 8 , 69 ( Se e Ta bl e 5 0 - 21 . ) Th is is t r u e e ve n t h ou g h p r ot am i ne in
N P H b i nd s r e gu l ar in su l in i n vi t r o.
Regular Plus Lente or Ultralente
I n co n tr a st to t he re g ul a r – N P H mi xt u r e s , t h e r a pid ac t io n o f re g ul a r i ns ul in is bl u nt e d
s i gn i fi ca n tl y wh e n p re mixe d wi t h L en t e in s ul in . Th e e xc e ss zin c i n L en t e p r e pa r a ti o ns b i nd s t he
r e g ul a r i ns ul i n, co n ve r ti ng i t t o a n i n te r me di a t e - ac t in g fo rm . Th is ef f ec t i s o bs e r ve d e ve n wh e n
t h e t wo in su li ns a re mi xe d j us t b e fo r e i nj ec t io n ; ho we ve r , t h e c li ni ca l i mp or t a nc e o f th is ef f ec t
s e em s t o b e mi n im al . 69 , 7 9 S im il a r ch a ng es oc cur wh e n r e gu la r in su li n i s m i xe d wi t h U l t ra le n te
i n su li n .
Table 50-21 Compatibility of Insulin Mixtures
Mixture
Proportion
Comments
Regular +
NPH
Any
proportion
The pharmacodynamic profiles of regular and NPH
insulin are unchanged when premixed and stored in
vials or syringes for up to 3 months. In contrast, the
rapid action of regular insulin is significantly blunted
when mixed with Lente or Ultralente insulin. The
excess zinc in Lente preparations binds the regular
insulin, converting it into an intermediate-acting form.
When the two insulins are mixed just before injection,
the clinical importance of this effect appears to be
minimal.
Regular +
Lente
<1:1
Lispro +
NPH
Any
proportion
The absorption rate and peak concentration of lispro is
blunted when mixed with NPH; however, total
bioavailability is unaltered. The manufacturer
recommends mixing the two insulins just before
injection.
Lispro +
Ultralente
Any
proportion
Ultralente does not alter the pharmacokinetics of lispro.
Regular +
normal
saline
Any
proportion
Use within 2–3 hours of preparation.
Regular +
insulin
diluting
solution
Any
proportion
Stable indefinitely.
Insulin
glargine
Do not mix
with other
insulins
Pharmacodynamics could be modified.
Rapid-Acting Insulin Plus NPH
I n su l in li sp r o a nd as pa r t a r e c om p at i bl e wi t h h uma n N P H i n su li n m an u fa c tu r e d b y E li Li l l y a n d
C o m pa n y ( H um ul i n N ) and N o vo N o rd is k ( N o vo li n N ) , r es p ec ti ve l y. H o we ve r , r e la ti ve t o l is p ro
a n d a sp a r t a lo ne , th e a bs o r pt i on ra t e i s sl o we d an d th e p e ak c o nc en t r at ion s a r e b l un t ed . Th e
t o t al bi o a vai la b il i t y i s u na l t er e d . Th e m a nu f ac t ure r s re co mm en d m i xi n g th e t wo in s ul in s j us t
b e f o re ad mi ni s tr a ti o n, wh i ch s h ou l d b e sc he d ul ed 1 5 mi n ut es be f o re me al s . Th e co mp a ti b il it y
o f li sp r o a n d as p ar t wi t h o t h e r b ra n ds of hu ma n NP H i ns u li n o r an im al so ur c e N P H i s
u n kn o wn . 6 9 , 8 0
Rapid-Acting Insulin Plus Lantus
Th e l o ng - ac t in g L an t us m us t no t b e m i xe d wi t h an y o t he r in su l in s. I f L an tu s i s m i xe d o r di l ut e d
wi t h o t he r in su l in s, it s pH wi l l b e i nc r ea se d , wh i ch wi l l af f ec t i ts ab s or p ti on ki n et ic s . Th e on se t
o f ac t io n a nd du r a ti o n o f e f f ec t ma y b e a l te r ed unp r e di c ta bl y. 8 1
Rapid-Acting Insulin Plus Ultralente
Th e i ns u li n c on ce n t ra t ion - t im e c u r ves fo r l is p r o a n d h um a n U l t ra le n t e ins u li n ( H u mu li n U )
a d mi ni s te r ed se pa r a te l y o r in co mb i na t io n a r e vi rt u a ll y su p e ri mp os ab l e. Th e r e fo r e, U l t ra le n te
i n su li n d o es no t m od i f y th e ph a rm ac ok i ne ti cs of lis p r o. A lt h ou g h li sp r o –L en t e m i xt u r e s h a ve
n o t b e en s t ud i ed , o n e wo u ld an t ic ip a te si mi la r r es u lt s . N e ve r th e le ss , L il l y r e co mm en ds mi xi n g
t h e t wo in su li ns ju s t b ef or e in j ec ti o n. 8 0 No da t a ar e a va il ab l e r e ga r di n g t he s ta bi l it y o f i ns ul i n
a s pa r t wi t h c r yst a ll in e i ns u li n p r od uc t s; t he r ef o r e, t h e y s ho u ld be a voi d ed a cc o rd i ng to t he
m a nu f ac tu r e r .
Phosphate-Buffered Regular or NPH Plus Lente or Ultralente
W hen p ho sp h at e -b u f fe r ed i ns ul in s (e . g. , N P H o r V e l os ul i n B R , N o vo N o r di sk ) a re m i xe d wi t h
L e n te o r U l t ra le n te in s ul in s , t h e p ho sp h at e b i nd s wi t h zi n c a n d co n ve r ts the s e i ns ul in
p r e pa r a ti o ns i n to m o r e ra p id - ac t in g fo rm s . 6 9 Th is p ro b le m is no t l ik e l y to b e c li n ic al l y
e n co u nt e re d wi t h Ve lo s ul i n B R b ec au se it is ge ner a l l y re se r ve d fo r u se in i n su li n p um p s.
P . 5 0 -3 0
Insulin Glargine
I n su l in gl a rg i ne is a lo n g - a c ti n g a na lo g th a t is so lu b le a t p H 4 . 0 ; i t is de sig n e d t o p r ec ip i ta t e
wh e n i n je ct e d i nt o t h e ne u t r al p H o f s ub cu t an e ou s ti ss ue . Be ca us e a l l o th e r i n su li n p r o du ct s
h a ve a p H of 7. 0 , i t c an no t be mi xe d wi t h a n y o f th e m. 8 1
Evaluating Fasting Hyperglycemia
A. H . i s i n s t ru c t ed t o i n je c t 14 un i t s N P H a lo n g w i t h 7 un i t s r e gu l a r in su l i n b e f o re
b r e a k fa s t a n d 6 un i t s NP H p l u s 3 un i t s r e gu l a r i n s ul i n b e f o re d in n e r . Tw o w e e ks la t e r ,
s h e re t u r n s t o th e c l i nic w i t h th e fo l l ow in g bl oo d g lu c os e t re n d s :
Time
Glucose Concentration (mg/dL)mmol/L
7 AM
140–180
7.8–10.0
Noon
120–140
6.7–7.8
5 PM
90–130
5.0–7.2
11 PM
90–120
5.0–6.7
3 AM
60–90
3.3–5.0
S u b j ec t i ve l y, A. H . f e e l s s u bs t a n ti a l l y b e t t e r . He r e ne r g y l e ve l i s be g i nn i n g to r e tu r n t o
n o r m a l a nd h e r n o ct u r ia h as d im i ni s he d , b u t sh e oc c as i o na l l y g e t s u p o n e o r tw o t i me s
n i g h t l y t o u r i n a t e . A. H . h a s a l s o n o ti c ed t ha t ni g h t ma r e s o r “ sw e a ts ” s o m e ti me s aw ak en
h e r . Wh e n t h i s o cc u r s , s h e g e ne r a l l y h a s s o met h i n g to ea t be c au s e s he i s “ fa m is h e d. ”
S h e is a bl e to ge t ba c k t o s le e p b u t w ak es u p th e ne x t m o r n in g w i t h a “ s p li t t i ng
h e a da c he ” a n d a “ h un g - o ve r ” f ee l i ng . A. H . ' s w e i g h t re ma i n s t h e s am e, a n d s he ha s be g un
t o d e ve l op so m e c on s is t e n c y i n h e r d i et a r y p a t t e r n s w i t h th e h e l p o f a d ie t i t ia n . S h e i s
c o n su m i ng tw o to t h re e c a r b oh yd r a t e s e r vi n g s p e r me a l a nd i s f e el i n g m o r e c o mf o r t a bl e
i n h e r a b il i t y t o c o u n t ca r b o h yd r a t e s . T h e A 1 C fr o m h e r l as t vi s i t i s 8 . 3%. T h e n ew g oa l is
t o a ch i e ve bl o od g lu c os e co n ce n t r a ti o ns < 15 0 m g / dL p r ep r a nd i a ll y. E va l u a t e A. H . ' s b l oo d
g l u c os e va lu e s. W ha t ar e p o ss i bl e c a us e s o f A. H . ' s fa s t in g h yp e r g l yc e m i a?
A . H . ' s pr e lu nc h , p r ed i nne r , an d b e dt im e b l oo d g lu c os e c on ce n t ra ti o ns have i mp r o ve d
c o ns id e ra b l y, i nd ic a ti n g t h a t h e r mo r n in g d os e o f r e g ul a r i ns ul in , m o r ni ng d os e o f N P H , a nd
e ve n i ng do se of r eg ul a r in s ul in a re ad e qu a te (s e e Ta b l e 5 0 - 19 ) . He r F P G c o nc en t r at i on
r e m ai ns el e va te d , a nd he r p re l un ch co nc en t r at i on co u ld be im p ro ve d . W he n e val u at i ng m o rn i ng
h yp e r gl yc em i a, s e ve r al ca u se s m us t b e c on si de r ed :

A n i ns uf f ic ie n t d os e o f eve n i n g N P H . If t he e ven in g do se of N P H is i ns u f fic i en t , h ep a ti c
g l uc os e o u tp u t d u ri ng t he f as t in g s ta t e wi ll be e xc es si ve , th e r eb y p r od uc in g
h yp e r gl yc em i a.

A n i ns uf f ic ie n t d u ra t io n o f ac t i o n o f t h e e ve ni n g d o se of N P H (s e e f ol l o win g
d i sc us si on ) .

R e a c ti ve h ype r gl yc em ia i n re s po ns e t o a no c tu r na l h ypo gl yc em ic ep is o de ( S o mo g yi
e f f ec t ) .

A n e xc e ss i ve b e dt im e s na ck .

Th e d a wn p he n om en o n (s e e Q u es t io n 1 9 ) .
Somogyi Effect or Rebound Hyperglycemia
Th e p r es e nc e o f n o rm og lyc e mi a a t be d ti me , l o w bl o od gl uc o se c o nc en t r at io n s a t 3 am , a nd
s ym p to ms o f no ct u r na l hyp o g l yce mi a (n ig h tm a re s, s we a t in g , h un g er , m o r ni n g h ea d ac he ) in
A . H . a re co ns is t en t wi t h a r e bo un d h y pe r gl yc e mic r e ac t io n i n t h e mo r n in g ( i . e .,
p o st h yp og l yce mi c h yp e rg l yc em ia ; So mo g yi e f f ect ) . 8 2 Th e o r e t ic a ll y, th is e f f ec t o cc u rs af t e r a n y
e p is o de of s e ve r e h yp ogl yc em i a a nd is s ec o nd a ry t o a n e xc e ss i ve i nc r eas e i n g l uc os e
p r o du c ti on b y th e l i ve r t ha t is ac ti va t ed b y in su li n c ou n te r - r eg u la t o r y h o rmo n es s u ch as
c o r ti so l , g lu ca g on , e p in ep h r in e , a nd g ro wt h h o rmo n e . 8 3 Th e wa n i n g e f fe ct s of th e e ve n in g
d o se of N P H in su l in al so m a y c o nt r i bu t e b ec au se i ns u li n i s n ee de d to s u pp r e ss h e pa t ic
g l uc os e o u tp u t d u ri ng t he f as t in g s ta t e . Th e e xi s te n ce of r eb o un d h yp e rg lyc e mi a h a s b ee n
q u es t io n ed . 84 H o we ve r , a s G e ri ch 85 p oi nt s o u t, th e s t ud i es ’ f in d in gs c a n b e e xp l ai n ed b y th e
a b se nc e o f c o un t er - r e gu la t o r y r es po ns es in so me p a ti e nt s o r h yp e r in su li ne m ia , wh ic h
c o un t e ra ct s t h e e ff e ct s of g lu ca g on , e p in e ph r in e , a n d c o rt is o l. As ym p to mat i c n oc t ur n al
h yp o g l yc em i a ca n o cc u r i n 33 % o f p a ti e nt s t ak i ng e ve n in g d os es o f i ns ul in a n d ma y a cc ou n t
f o r m o r ni ng h yp er g l yc emi a in >1 0 % o f p at i en ts . An o t he r po t en t ia l c on se q ue n ce of no c tu r na l
h yp o g l yc em i a is p ro lo n ge d in su li n re si s ta nc e ( p er h a ps a co ns e qu e nc e o f g l uc os e t o xi c i t y) , a s
s i gn i fi ed b y hi gh p os tb r ea k fa s t g lu co se c o nc en t r at i o ns . B y c o rr e ct i ng th e n o ct u r na l
h yp o g l yc em i a, no r ma li za t i o n o f A . H . ' s f as t in g h ype r g l yce mi a a ls o m a y b e a c hi e ve d. Th e
f o l lo wi n g a r e th e ra p eu t ic o p ti o ns :

D e c r ea se th e e ven in g d os e o f N P H b y 2 to 3 u ni ts an d h a ve A . H. co n ti nue t o m on i to r
b l oo d g l uc os e c on ce n t rat i o ns a t 3 A M.

I f A . H . i s wi l l in g to gi ve h e r se l f t h re e i nj ec t io ns of i ns ul i n, sh if t th e e ve n ing i nj ec t io n o f
N P H ( 6 un i ts ) fr om p re d in n e r t o b e dt im e . Th i s p re f e r re d m e th o d e ff ec t i vely s h i ft s t h e
p e ak ac ti o n o f N P H t o t he e a rl y mo r ni n g wh e n she wi l l be a wa ke an d d ec re a se s t h e r is k
o f no c tu r na l h yp o gl yc em ia . 6 5 , 8 6 Th i s p ea k a ct i on a ls o c o r re sp o nd s t o t h e d a wn
p h e no me no n (s ee Q u es tio n 19 ) an d t h e b r ea kf as t m ea l .

I f A . H . i s wi l l in g to gi ve h e r se l f t h re e i nj ec t io ns , a n o th e r o p ti on is to ch ang e f ro m N P H
t o in su l in gl a rg i ne (L a nt us ) as he r b as a l i ns ul in , si n ce th is p ro d uc t a ls o i s a ss o ci at e d
wi t h l es s n oc t u rn al h ypog l yc em ia . 58 , 67 , 87 D ec r ea s e t he da i l y d os e of N PH b y 2 0 % a nd
g i ve 18 un i ts o f La n tu s at b ed t im e o r e ve r y m or n in g , d e pe n di ng on A . H . 's p r e f er e nc e .
R e m in d A. H . th a t t h e d os e o f La n tu s ca n no t b e m i xe d wi t h he r R eg u la r in s ul in .
Midmorning Hyperglycemia
E va l u a t e A. H . ' s n o on b lo o d gl u c os e c o nc e n t ra ti o n .
Mi d m o r n in g h yp e r gl yc emi a f re q ue n tl y r ep r es e nt s t h e m a xi m um gl uc os e e xc u rs i on in pa t ie n ts
wi t h d i ab e te s a nd o ft e n is t he m os t di f fi cu l t t o m an a g e. Th e fo ll o wi n g a r e p o ss ib l e e xp l a na t io ns
f o r m i dm o rn in g h yp e r gl yc em i a:

A n i ns uf f ic ie n t d os e o f re g ul a r i ns u li n b e fo r e b r ea k fa s t.

P o o r s yn ch r o n y b e t we e n m ea l i n ta ke an d i ns u li n a c ti o n. Th i s co u ld be c au s ed b y
a d mi ni s t ra ti o n o f i ns ul i n j u st be f o re o r a f te r m ea ls o r a d e la ye d o ns e t o f ac t io n o f
r e g ul a r i ns ul i n d ue t o bi nd i ng wi t h in t e rm ed ia t e -ac t in g i ns u li n o r i n su li n -b lo ck i ng
a n t ib od i es . 49 Th e l a tt e r t wo e xp l a n a t io ns a re un lik e l y i n A. H . As di sc us sed i n Q u es t io n
1 4 , L e nt e i ns u li n , b ut no t N P H i ns u l i n, is m o r e li ke l y t o d el a y t he ph a rm aco l og ic
r e s po ns e t o re g ul a r i ns uli n . Be ca us e A. H . is a newl y d i a g n os ed pa t ie n t wi t h di a be t es , i t
i s u n li ke l y th a t s he ha s de ve l o pe d s ig ni f ic an t c o nc e nt r a ti o ns o f i n su li n -b l oc ki n g
a n t ib od i es .
P . 5 0 -3 1

A n i ns uf f ic ie n t d os e o f eve n i n g N P H in su l in to sup p r es s h ep a ti c g lu co se pr o d uc t io n
( g l yc og en o l ysi s a nd gl uco n e og en es is ) du r in g th e f a s ti ng st a te o r t he da wn p h en om e no n
( s e e Q u es t io n 1 9 ) .

E xc e s s i ve c a rb oh yd r a te i n ge s ti on a t b r ea kf as t .

I n c re as e d p e ri ph e r al re sis t an ce t o i ns ul in ac t io n ca u se d b y h ig h f a st i ng glu c os e l e vel s
( g l uc os e t o xi c i t y) .
W hen e va lu a ti ng mi dm o rn i ng h yp er g l yc e mi a, i t is i mp o r ta n t t o r em e mb e r th a t th e F P G
c o nc en t r at i on c a n co n t rib u t e u p t o 5 0% o f t hi s p la sm a g l uc os e e xc u r s io n . Th e r e f o re , t h e
p r i ma r y ap p r oa ch to t he c o nt r o l o f h yp e rg l yce m i a m a y be to no r ma li ze t he f a st i ng gl uc os e
c o nc en t r at i on .
Th i s sh ou l d b e t he ap p r oa c h us e d f o r A . H . If co n tr o l o f he r fa st i ng h ype r g lyc e mi a d o es no t
c o r re c t t he mi dm o rn i ng hyp e r g l yce mi a , t he f ol lo wi n g in t e r ven t io ns m a y be c o ns id e re d :

I n c re as e th e d os e o f re gu l a r o r i ns u li n l is p ro o r in s ul in as p ar t be f or e br ea k fa s t.

I n j ec t t h e mo r ni n g d os e o f r eg u la r i ns u li n 4 5 t o 60 mi n ut es be f o re b re ak f as t in an
a t t em p t t o ma t ch pe ak ins u li n c on ce n t ra t io ns wi t h p os t me al gl uc o se e xc u rs i on s. I f t hi s
m a ne u ve r i s us e d, t he pa t i en t s ho u ld be wa r n e d o f po ss ib l e h yp og l yce mia b ef o r e
b r e ak f as t .

A l t e r t h e ca r b oh yd r a te co n t en t o f th e m ea ls . Th is m a y in cl ud e d e cr e as in g t h e a mo u nt o f
c a r bo h yd ra t e i n t h e b re ak f as t m ea l , c ha ng i ng th e t yp e of ca r bo h yd r at e i nge s te d , o r
a d di n g f ib e r to th a t me a l t o m i nim i ze gl uc os e e xc u r s io ns .
Preprandial Hypoglycemia –Use of Insulin Lispro and Aspart
A. H . a g r e e s t o gi ve h e rs e l f th r e e i n je c t io n s o f i n s u li n a s f ol l ow s : 1 4 un i t s N P H /7 un i t s
r e g u l a r i n su l i n b e fo r e b r e a k fa s t ; 3 un i t s r e g ula r i n su l i n b e fo r e di n ne r ; a n d 6 un i t s N P H a t
b e d t im e . Tw o w e ek s l a te r , s he b r in g s i n h e r blo o d gl u c os e c o nc e n t ra ti o n r ec o r d s :
Time
Glucose Concentration (mg/dL)mmol/L
7 AM
110–120
6.1–6.7
Noon
60–110
3.3–5.5
5 PM
90–110
5.0–6.1
11 PM
90–110
5.0–6.1
3 AM
80–110
4.2–6.1
A. H . f e e l s th a t s h e i s now “ b ac k t o no r m a l. ” Sh e ha s no si g n s o r s ym p t o m s o f
h yp e r g l yc e m i a , a n d h e r w ei g h t h a s r e ma i ne d st a b l e. O c ca s io n a ll y, s h e b ec o me s
h yp o g l yc e m i c be f o r e l un c h , b u t th i s m os t o f ten o cc u r s w he n he r l un ch i s d e la ye d
b e c au s e o f a b us y w o rk s c he d u le . E va lu a t e A. H . ' s bl o o d g l uc o se t r end s . Wh a t c o ul d be
t h e ca u se o f h e r p r e l unc h h yp o g l yc e m i a an d how c o u ld sh e be ma n age d ? Is t he us e o f
i n s u li n li s p r o a n o p t io n? H ow s ho u l d i t be us ed ?
A . H . ' s bl oo d g l uc os e c onc e nt r a ti o ns i n di ca t e t ha t h e r ba si c i ns ul in r eg im en is ge n e ra ll y
a d e qu a te to ac hi e ve th e o ve r a ll go a l o f p r ep r an d ia l bl oo d g l uc os e c on ce n tr a t io n s o f < 12 0
m g /d L . No t e t ha t c o r re c tio n of A . H . 's F P G c on c ent r a t io n u l ti ma t el y co r r ec te d he r m i dm or n in g
h yp e r gl yc em i a. In f ac t, i f o n e we r e t o e va lu a te A .H . ' s bl o od gl uc os e c o nc en t r a ti o ns f r om t he
p r e vi ou s vis it , i t is e vi d en t t ha t t h e p r eb r ea k fa st d o se of r eg u la r i ns u li n wa s wo r ki n g ( se e
Q u e s ti o n 1 5 ) . Th a t is , e ve n th o ug h t h e a bs ol u te bl o od gl uc o se c o nc en t r at io n at mi dm o rn i ng
wa s h i gh , i t wa s a p p ro xi m a te l y 30 mg / dL le ss tha n th e fa st i ng gl uc os e co n ce n t ra t io n o f 1 6 0
m g /d L . Th is d om i no ef f ec t on bl oo d g l uc os e c on ce n t r at i on s em p ha si ze s th e im po r t an ce of
c o r re c ti ng o ne bl oo d g l uc os e c o nc en t r at io n a t a ti m e.
Th e h yp o gl yc em ia A . H . is e xp e r i en ci ng b ef o re lun c h co u ld be ca us ed b y in s uf f ic ie n t
c a r bo h yd ra t e i n t a ke at br e a kf as t , a n e xc e s si ve do s e o f r e gu l ar in su l in , o r t h e r e la t i vel y l on g
d u r a ti on o f ac t io n o f re gu l a r i ns ul i n. Th us , th e p ro b le m c ou l d b e r es ol ve d b y a ug me n ti n g A . H . ' s
b r e ak f as t m ea l , lo we r i n g t h e m or n in g d os e o f re gu l a r i ns ul i n, o r a dd in g a m i dm o rn in g s na ck .
A n o t he r op ti o n is t o us e i n su li n l is p r o o r a sp a r t ra t h e r t ha n re gu l a r i ns ul in b ec au se it s o ns e t o f
a c ti o n is mo r e r a pi d t h an t h a t o f r e gu la r in su l in . To ca lc u la t e h e r i ns ul in t o c a rb o h yd ra t e r a ti o ,
d i vi de t he nu mb e r 5 00 by h e r to t al da i l y d os e o f in s ul in ( TD D ) :
5 0 0 /3 0 = 17 g C H O p e r un i t o f i ns u li n
S i n ce m os t s i ng le - se r vi ng s o f c a r bo h yd ra t e c on t ai n 15 g ra ms , A . H . s ho u ld u se 1 u ni t fo r e ve r y
1 5 g ra ms o r s i ng l e se r vin g of ca r bo h yd r at es sh e c o ns um es at ea ch me al . I n su l in li sp r o o r
a s pa r t a r e m o re c o n ven ie n t l y a dm i ni st e r ed ju st be f o r e a m ea l . H o we ve r , A . H . mu s t b e wa r n e d
t o in j ec t i ns ul i n li s pr o o r a s pa r t o n l y i f s h e wi l l b e e a ti n g wi t h i n 1 5 mi n ut es o r s o , b ec a us e i ts
o n se t o f ac ti o n is qu i te ra p id . B ec au se in su li n l isp r o an d a sp a r t h a ve a b ri e f er d ur a ti o n o f
a c ti o n t ha n re g ul a r i ns ul in , t he y ca us e fe we r p os tp r a nd i al h ypo gl yc em ic ep i so d es , a lt h ou g h
t h e ir e ff ec t on A 1 C is com p a ra bl e . 5 3 , 8 8
Supplemental Insulin
A. H . a l s o no t i ce s th a t he r p r e p ra n d ia l bl o od g lu c o se co n ce n t r a ti o n s in e x pl i c ab l y e x c e e d
t h e new g oa l o f 1 20 mg/ d L on o cc as i o n. S om e ti m e s t h e y a r e a s h ig h as 2 00 mg / d L.
E va l u a t e A. H . ' s b l oo d gl u c os e t r en d s. H ow sh ou l d oc c as i on a l p r e p r and i a l g l uc o se
c o n ce n t r a ti o ns t ha t exc e e d t h e d es i r e d g oa l of 1 2 0 m g/ d L b e m a na g ed ?
O n c e t h e b as ic do se of i n s ul in ha s b e en es ta b li sh e d , o ne c a n b eg i n t o t ea c h A . H . h o w t o
a d ju s t h e r d os e o f i ns ul in wh e n p re p ra n di al bl o od g lu co se co nc en t r at i on s f a ll ab o ve o r be l o w
t h e ra n ge of bl o od gl uc os e c on c en t ra t io ns t ha t ha ve b ee n e s ta bl is h ed as h e r go al o f t he r ap y
( 7 0 to 12 0 m g/ d L ). Two m e th o ds o f s u pp l em en t ing d os es of in su li n c a n be us e d i n t hi s
s i tu a ti o n: co mp en s at o r y i n su li n d os e s a nd an t ic ipa t o r y in su l in do se s 6 5 ( Ta b le 50 - 2 2 ).
C o m pe ns a to r y i ns ul i n d os es a re us ed t o co mp e nsa t e fo r u n us ua l l y h i gh or l o w p r e pr a nd i al
b l oo d g l uc os e c on ce n t rat i o ns . To re - em ph as i ze , th i s as su m es t h e re a re no u nu su a l ch a ng es in
t h e p a ti e nt ' s o ve r a ll di e t o r e xe r c is e p a tt e r ns . Ma n y c li n ic ia ns fa vo r in su l in l is pr o or as pa r t
o ve r r eg u la r in su li n b ec au s e t he i r a ct i on is b r i ef a n d p a ti e nt s d o n ot h a ve t o wo r r y a bo u t
r e s id ua l e f f ec ts 3 t o 4 h ou r s a f te r it s i nj ec t io n . Thi s i s p a rt ic u la r l y va lu ab le wh e n su pp l em en t al
d o se s o f i ns ul i n a r e n eed e d a t b e dt im e .
Th e p a ti e nt ' s s en si t i vi t y t o in su l in , a s r e fl ec t ed by h i s o r h e r to t al da il y do s e o n a u n it / kg ba si s
i s a ma jo r de t e rm in an t of a n y al g o ri t hm d e ve lo ped . P r e vio us l y, i t wa s a d vi s ed th a t 1 to 2 u ni ts
o f su pp l em en t al in su li n sh o ul d b e gi ve n f o r e ac h 3 0 to 50 mg / dL el e va ti on a b o ve t he t a rg e t
l e ve l . H o we ve r , t hi s r el a ti o ns hi p wa s o bs e r ve d t o a p pl y o nl y t o a pe r so n o f a ve r a ge s i ze o n
a ve r a ge do s es o f i ns u li n ( i . e. , th e 7 0 -k g p a ti en t on 5 0 U / d a y o f i ns u li n ) . A ve r y s m al l p e rs on on
1 0 U /d a y o r a ve r y ob ese i nd i vid u al wi t h t ype 2 di a be t es on 10 0 U /d a y has
P . 5 0 -3 2
d i f fe r e nt r es po ns es to a g i ve n d os e o f i ns u li n . A n a l te r n at i ve m et h od of est i ma t in g t h e d r op in
a p e rs on ' s b lo o d g lu co se p e r u n it of r eg u la r (o r r ap i d -a c ti ng ) in su li n i s t h e “ 1 5 00 R ul e . ” 6 0 Th e
1 5 0 0 R u le wa s d e ve lo p ed b y P au l Da vi d so n , MD , i n At l an t a, G e o rg ia , du r in g th e 1 9 90 s. Th e
d e r i ved va lu e i s r e fe r r e d t o as t h e “ se ns i ti vi t y f act o r ” :
Table 50-22 Guidelines for Dosing Insulin
Basic Insulin Dose
First adjust the basic insulin dose (i.e., the dose that the patient will be instructed to take
daily). This assumes that diet and physical activity are stable. Set a reasonable goal initially.
This may mean the upper limits of the acceptable concentrations may be high initially (e.g.,
<200 mg/dL). Move toward a more ideal goal slowly.
Only adjust insulin doses if a pattern of response is observed under stable diet and exercise
circumstances. That is, the same response to insulin is observed for ≥3 days. It is important
to verify the stability of diet and exercise. Consider adjusting these variables as well.
Unless all levels are >200 mg/dL, try to adjust one component of insulin therapy at a time.
Start with the insulin component affecting the fasting blood glucose concentration. This
glucose level often is the most difficult to control and often affects all other glucose
concentrations measured throughout the day.
Adjust the basic insulin dose by 1–2 U at a time. The amount prescribed is based on the
individual patient's response to insulin. This can be determined by looking at the patient's
total daily dose using the “500 Rule”(see the following, and Table 50-14).
Supplementary Insulin Doses
Once the basic dose of insulin has been established, supplemental doses of rapid- or shortacting insulin can be prescribed to correct preprandial hyperglycemia. For example, if the
goal is 140 mg/dL, and the glucose value is 190 mg/dL, administer an additional unit of
insulin lispro. Supplemental doses also can be used when the patient is ill (see Table 50-24).
Algorithms for supplemental doses are based on the patient's sensitivity to insulin using the
“1500 or 1800 Rule” (see Table 50-14).
If premeal glucose concentrations are <60–70 mg/dL, the dose of lispro, aspart or regular
insulin administered before the meal is ↓ 1–2 U; insulin administration is delayed until just
before the meal; the meal should include an extra 15 g of glucose if the value is <50 mg/dL.
If supplemental doses before a given meal are required for ≥3 days, the basic insulin dose
should be adjusted appropriately. For example, if a patient taking lispro before meals
requires an extra 2 U before lunch for ≥3 days, 2 U should be added to the prebreakfast
dose.
Anticipatory Insulin Doses
The basic insulin dose is increased or decreased based on the anticipated effects of diet or
physical activity.
Increase lispro/aspart or regular insulin by 1 U for each additional 15 g of carbohydrate
ingested (e.g., holiday meal) or decrease the usual dose by 1–2 U if the meal is smaller than
usual (see Table 50-14).
See Table 50-23 for recommended insulin adjustments for exercise.
1 5 0 0/ C u r re n t To ta l I ns u lin D o se = S e ns it i vi t y Fa ct o r
1 5 0 0/ 3 0 = 5 0
Th u s , 1 u ni t o f re g ul a r i ns u li n f o r A. H . wi l l d r op he r bl o od gl uc os e l e ve l b y a b ou t 5 0 m g /d L .
Th e 1 5 00 R ul e h as p ro ve d to be a val ua b le wa y t o in i ti a te an al g or i th m fo r su p pl em en t al
i n su li n . Pe op l e wi t h a l owe r s e ns i ti vi t y f ac t or ( hig h e r i ns ul i n r e qu i re me n ts ) t ypi c al l y a c hi e ve a
s ma l le r re d uc ti o n i n b lo od g lu co se pe r un i t o f i nsu l in co mp a re d wi t h t h os e wi t h a hi gh e r
s e ns it i vi t y fa c to r (l o we r in s ul in r eq u ir e me n t) . Th e r u le h as b e en m o d i f ie d to a n “ 1 80 0 Ru l e” f or
p a t ie n ts u si n g i ns ul i n li sp r o or as p ar t be ca us e t he s e i ns ul in s t e nd to d ro p t h e b lo o d g lu co se
l e ve l f as t e r a nd fa r t he r .
Th u s , an al go r i th m o f 1 u n i t o f r e gu l ar in su l in fo r e ve r y 5 0 m g/ d L e xc u r sio n ab o ve h e r g o al o f
1 2 0 m g/ d L is a r e as on a bl e pl ac e t o b e gi n . I f t h is d o se of in su l in is i ns u f fi ci e n t, on e c an
i n c re as e t h e d os e o f i nsu l in o r d ec r ea se th e bl ood g lu co se e xc u r si on r equ i r ed pe r un i t o f
i n su li n d os e . Su pp l em ent a r y i ns ul i n d os es a ls o ar e us e d f o r si ck da y ma na g em e nt (s e e
Q u e s ti o n 3 1 ) . Th e f o ll o wi n g i s a n e xa m p le of an a l go r i th m f o r A . H . :
Glucose Concentrations (mg/dL)
Regular Insulin
<80
1 unit less
80–120
Usual dose
120–170
1 unit extra
170–220
2 units extra
220–270
3 units extra
270–320*
4 units extra
*Check urine ketones. If urine ketones are positive and blood glucose concentrations
remain >240 mg/dL for ≥12 hours, call the physician for directions.
A n t ic i pa t or y i ns ul i n su p pl e me n ts a r e p r es c ri be d in a nt ic i pa t io n o f a n i mme d ia t e e ve n t t ha t is
l i ke l y to al t e r a p a ti e nt ' s r e s po ns e t o i ns u li n . Th i s i nc l ud es an un us u al l y lar g e or sm al l m ea l o r
e xe r c i s e ( se e Ta bl e 5 0 -22 a nd Q u es ti o n 3 0 ) .
“ S l i di ng sc al e ” r e fe r s t o a n al go r i th mi c m et h od of a d ju st i ng do se s o f S C ra p id - o r sh o r t -a ct i ng
i n su li n a cc o rd i ng to bl o od g lu co se te s t r es u lt s. S li d in g s ca le s t yp ic a ll y a r e u se d fo r
h o sp i ta li ze d pa ti e n ts wi th d ia be t es wh o se in su l in r e q ui r em en ts ma y va r y d r a st ic a ll y b ec au se of
s t r es s ( e .g . , i nf ec t io n s, su r g e r y, a n d a n y a cu t e i lln e ss ) , i na c ti vi t y, o r va r iab l e c al o ri c i nt a ke
( s e e Q u es t io n 3 4 ) . H o we ve r , a s p re vi o us l y n o t ed , s li d in g sc a le s a ls o a r e us e d r o ut i ne l y b y t ype
1 p at i en ts on in t en si ve in s ul in t he r ap y.
Typ i c a l l y, b lo o d g lu co se c o nc en t r at i on s a r e me asu r e d e ve r y 4 h o ur s , a nd r a p id o r sh o r t -a ct i ng
i n su li n i s a dm in is t e re d as p re sc r ib e d. S li di n g sc al e s sh o ul d b e i n di vi du a lize d t o t h e p at i en t ' s
k n o wn se ns i ti vi t y to in s ul i n a nd ad j us te d acc o rd in g to hi s o r h e r re sp o nse . G e ne r al l y, 1 t o 2
u n i ts o f l i sp r o, as pa r t or r e g ul a r i ns ul i n a r e a dm ini s te r e d f o r e ve r y 30 to 50 mg / dL ab o ve a
p r e de t e rm in e d t a rg e t g luc os e c o nc en t r a t io n (e . g ., 1 8 0 mg / dL ) (s e e Ta b l es 5 0 - 22 an d 5 0 -2 4 ) .
Th e p r in ci p le s a pp l ie d i n t h is c as e a r e s im il a r t o th o se us ed in es t ab li sh i ng su p pl em e nt a l
d o se s o f i ns ul i n as p re vio u sl y d es cr i be d .
Dawn Phenomenon
R . D . , a 3 7 - ye a r - o l d m a n, h a s h ad t yp e 1 d i a b e te s si n ce a ge 14 . O ve r th e pa s t 2 ye a r s , h e
h a s b e en ve r y w e ll c ont r o l l e d o n t h e f o l low i n g i n s ul i n re g im e n : 2 0 u ni t s La n t us ea c h
m o r n i ng w i t h 3 t o 4 u n it s i ns u l in l is p r o d e pe nd i n g o n ca r b o h yd r a t e i n t a k e b e fo r e m e al s .
O n t h i s re g im e n, h is b lo o d gl u c os e c o nc e n t ra ti o n s fo r t he pa s t 2 w e ek s ha ve b ee n as
f o l l ow s :
Time
Glucose Concentration (mg/dL)mmol/L
7 AM
140–170
7.8–9.4
Noon
100–120
5.5–6.7
5 PM
100–130
5.5–7.2
11 PM
115–140
6.4–7.8
3 AM
100–120
5.5–6.7
P . 5 0 -3 3
W h a t a r e th e li k el y c a u s e s o f R . D .' s fa s t in g h yp e r g l yc e m i a ?
A s di sc us se d i n Q ue st i on 1 5 , f as ti n g h yp e rg l ycem i a ma y b e t h e r e s u lt of i n su f fi ci e nt do se s o f
i n su li n i n th e e ve ni n g, a d e cl in e i n th e e f fe c t o f i ns u li n o ve r ti me , a n d, po ss i bl y, r ea ct i ve
h yp e r gl yc em i a. In R . D . 's c as e , t he da wn p h en ome n o n al s o mu s t b e co ns id e r ed . 89 Th e da w n
p h e no me no n i s a ri s e in t h e b l oo d g lu c os e co nc en t r a ti o n t ha t o cc u rs be t we e n 4 an d 8 A M a f t e r
a p h ys i o l o gi c n ad i r i n t he b lo od gl u co se c o nc en tr a t io n th a t oc c ur s b e t wee n m i dn ig h t a n d 3 A M.
Th i s 30 t o 4 0 mg / dL in c re a se in th e m o rn i ng bl ood g lu co se co nc en t r at i on c a nn o t b e a t t ri bu t ed
t o in c re as es in co un t e r - re g ul a to r y h o rm on es se co n d ar y t o a n a n te ce d en t h yp o g l yc em ic e ven t ,
b u t i t m a y be se co nd a r y t o r is in g g r o wt h ho r mo ne l e ve ls . Thi s p h en om en on is in co ns is t en t l y
o b se r ve d i n i nd i vi du a ls wi t h t yp e 1 a nd t ype 2 d ia b e te s a s we l l as n o nd iab e t ic i n di vi du a ls ;
f u r t he r mo r e , i t is in co ns is t en t l y pr e se n t f r om o n e d a y t o t h e n e xt . 9 0
R . D . ' s 3 A M b l o o d g lu cos e c on c en t ra t io n i n di ca te s th a t p os th yp o gl yc em ic h ype r g l yc em i a is an
u n li ke l y ca us e o f h is f as ti n g h yp e rg l yce mi a . Th us, t h e mo d es t i nc r ea se in h i s b lo od gl u co se
c o nc en t r at i on be t we e n 3 a n d 8 A M m a y be a tt r ibu t e d t o t h e wa n i n g e ff ec ts o f i ns ul in o r t he
d a wn p h en om e no n . I n b ot h ca se s, an in c re as e i n R . D . ' s da i l y d os e o f i n sul i n g la r gi n e wo ul d b e
i n di ca t ed . A no t he r op ti on wo u l d b e t o s wi t c h R. D. t o a n i ns u li n p um p . H e h a s d em on s tr a te d a
d e si r e a nd ab i li t y f or in te n si ve m a na g em en t wi t h m u l t ip l e d ai l y i n je c ti on s , f r e qu e nt bl o od
g l uc os e m on i to r in g , r e cor d - ke e pi n g sk il ls , th e a bil i t y to ma ke ap p ro p r ia t e in s ul in do s e
a d ju s tm en ts a nd acc u r ate ca r b oh yd r a te c o un t in g . Th e a d van t ag e to us in g a p um p is t he ab il i t y
t o p ro g ra m a n i nc r ea se in t he ba sa l i n fu si o n r a te a t ap p r o xi m at e l y m id n igh t . Be c au se it ta ke s 3
t o 4 h ou r s t o o bs e r ve a b i ol o gi c r es p on se fo l lo wi n g a ch a ng e i n t h e i nf u sio n r at e , t he r es po ns e
wo u l d oc cu r at ap p r o xi ma t e l y 3 t o 4 A M, wh e n t he d a wn ph e no me n on be gi n s. 9 1
Type 1 Diabetes in Children
Diagnosis and Clinical Presentation
J . C . , a 7 - ye a r - o l d , 3 0 - kg ( 9 5 th pe r c en t i l e) , 50 ” t a l l ( 9 0 th pe r c e nt i l e) g ir l , w a s b r o u gh t t o
t h e em e r ge n c y d e p a r t me n t ( E D ) b y h e r p a r e n ts b e ca u se o f n a us e a, vom i t i ng , an d a
p e r s is t e n t “s t o ma c h a ch e ” s ec o n da r y t o t h e f lu . F o r t h e p a st w e ek , J.C . h a d f l u li k e
s ym p t o m s , r es u l ti n g i n a 6 -l b w e ig h t l o ss . In i ti a l la b o ra t o r y va l u e s r eve a l e d a b lo o d
g l u c os e o f 60 0 m g /d L , s e r u m p H o f 6 .8 w i t h b ic a r b o na t e l e ve l o f 13 mE q / L , p l as m a k e to n e
l e ve l o f 5 . 2 m mo l / L, and p o si t i ve ke t o nu r i a . J .C . w a s di a gn o se d w i t h d i a be t i c
k e t o ac i do s i s se c o nd a ry t o n ew - o ns e t t yp e 1 di a b e te s . I n re t r o s pe c t an d o n f u r t he r
q u e s ti o n in g , J . C . 's pa re n t s re a l iz ed t ha t sh e pr o b a b l y h a d s ym p t o m s a s ea r l y a s 4 w ee k s
b e f o r e h e r h o s pi t a li za t io n . Wh i l e o n a d r i vi ng va c a t i o n, s he d ra n k l a rg e q ua n t it i e s o f
j u i c e a nd ha d t o s t op ho u r l y t o u r i n a t e. S he be g a n e xp e r i en c in g en u re s i s, w h i ch he r
p a r e n ts a t t ri b u te d t o he r i n c re a se d fl u i d i n ta ke . W ha t si g ns an d s ym p t o m s a r e c o ns i st e n t
w i t h t h e d i ag n os i s o f t yp e 1 d i ab e t es in a c h il d?
J . C . ' s p r es en t at i on is t ypi c al fo r a ch i ld ne wl y d i ag n os e d wi t h di a be t es wh o is b ro u gh t i n f o r
m e di ca l a t te n ti o n b ec au se o f s e ve re s ym p to ms rel a t ed to t he fl u . A n a cu t e vi r a l i ll n ess ca n
t r i gg e r a u to im mu n e d es tr u c ti o n o f t he pa n cr e as an d ab d om in al pa i n, wh i ch ma y m as qu e ra d e a s
g a st r o en t e ri ti s . A b do mi na l pa in is a co mm on p res e nt i ng s ym p to m o f d ia be t ic ke t oa ci do si s
( D K A ) . 9 2 J . C . 's we i g ht lo ss p ro b ab l y r ep r es en t s f l u id an d c al o ri c l os s se co n d ar y t o
u n co n t ro ll e d d ia b et es as we l l as de c re as e d c al o ric in t ak e f r om th e fl u .
A s il lu s t ra t ed wi t h J . C . , th e c o r re c t d ia g no si s o f di a be t es m e ll i tu s o f te n i s d e la ye d i n c h il d re n
b e ca us e p o l yu ri a i s in c orr e c tl y a t tr i bu t ed t o a u r ina r y t r ac t i n f ec ti o n o r e nur e s is ; a no r e xi a
o cc u rs r at h e r t ha n p o l yph a gi a ; a n d s ymp t oms of f a t ig u e, i r ri ta b il i t y, we ig ht l os s, de t e ri o ra t io n
i n s ch o ol pe r f or m an ce , an d en u re si s a r e a t t ri bu t ed t o “ e m o ti o na l ” p r ob l ems . A d ia g no si s o f
“ f a il u r e t o t h ri ve ” al so ma y d e la y t he di a gn os is of d ia b et es in a you ng ch il d , a l th o ug h t h is i s
n o t th e c as e f o r J . C. , wh o is ab o ve th e 9 0 th pe r ce n t il e i n we ig h t a n d h ei gh t f or ch il d r en he r
a g e . Th e s ym p to ms of po l yu r ia a re le ss o b vi ou s i n an in f an t a n d a r e f r equ e n tl y mi ss ed u nt il
m e ta b ol ic de r an g em en t h a s oc c ur r e d. U nl ik e J . C. , in f an t s f r eq u en t l y p r ese n t wi t h s e ve re
d e h yd ra t io n a n d m et a bo li c a ci d os is d e sp it e a n ega t i ve h is t o r y o f di a r rh e a o r si g ni fi c an t
vo m i ti n g.
Goals of Therapy
W h a t a r e th e go a ls o f th e r a p y f o r J . C . ? D o t he r e s u l ts o f t h e D C C T app l y t o c h i l d r en su c h
a s J. C . ?
Th e g o al s o f t h er a p y fo r c h il d re n s uc h a s J . C. and a do le sc e nt s wi t h d ia bet e s m el li t us ar e a s
f o l lo ws : ( 1 ) ac h ie ve no rm a l g r o wt h a n d d e vel o pm e nt , (2 ) ob t ai n o p ti ma l g l yc em ic c o nt r ol , (3 )
f a ci l it a te po si t i ve p s yc h os oc i al ad ju s tm en t to di abe t es , an d ( 4 ) p r e ve nt acu t e a n d ch r o ni c
c om p li ca t io ns . A tt ai n men t o f t he se go a ls re q ui r es a t r em e nd ou s a mo un t o f su pp o r t a nd
e d uc a ti o n f o r t he pa r e nts an d c a n b e b es t p r o vide d b y a mu l ti di sc ip l in a r y t e am o f
p r o f ess i on al s , i nc lu di n g a p h ys ic i an , n u rs e e d uc at o r , p h a rm ac is t , d ie ti t ia n, a nd ps yc ho so ci a l
e xp e r t .
G r o wt h s e r ves as an im po r t a nt c l in ic al in d ic at i on o f o ve ra l l g en e ra l h e al t h a n d we l l - be i ng in
c h il d re n wi t h d ia b et es . He i gh t an d we i gh t s ho u ld b e m e as u re d a t e ac h visi t an d p l ot t ed on
s t an d a rd g ro wt h g ri d s. I f, a t t h e t im e o f d i ag no si s, a c h il d h as fa ll e n b eh i nd i n h ei gh t o r we i g h t,
p r o mp t a n d a pp r op r i at e tr e a tm e nt sh ou l d q ui ck l y r e t u rn t he c h il d t o t h e a pp r o p ri a te pe r ce n ti le
a n d p a tt e r n o f g r o wt h . An o be se ch il d s ho u ld be e n co u ra g ed t o ac h ie ve a m o re ap p ro p r ia t e
p e r ce n ti le o f we i g h t g r adu a ll y o ve r a p er i od of seve r a l m o nt hs .
Th e D C C T d e m on s tr a t ed t h a t in t e ns i ve co n t ro l red u ce d t h e i nc id e nc e o f lo n g - te rm
c om p li ca t io ns in pa t ie n ts 1 3 yea r s o f a g e o r o ld e r; s imi l a r e vi de nc e i n ve ry yo u n g c h il d re n i s
l a ck in g . Th u s , t he A D A st a t es : “g l yce mi c g oa ls ma y n e ed to be mo di f ie d to t ak e i n to acc o un t
t h e fa ct th a t m os t c hi ld r en yo u ng e r t h an 6 o r 7 yea r s o f a g e h a ve a fo r m of ‘ h ypo g l yc em ic
u n a wa r e ne ss , ’ i n t ha t the y l ac k t h e co g ni t i ve ca pa c it y t o re co g ni ze an d r es p on d t o
h yp o g l yc em ic s ym p to ms a n d m a y b e at g re a te r ris k f o r t h e se q ue l ae of h yp o gl yc em i a. ” 93 J. C . ' s
p e di a t ri ci a n mu s t st r i ve fo r t he be st gl u co se c o nt ro l th a t s he , h e r f am i l y c ir c um s ta nc es , a n d
c u r re n tl y a va il a bl e t r e atm e nt r eg im e ns wi l l p er mit .
Insulin Therapy
H ow s h o ul d J. C . be s tar t e d o n i ns u l in ?
B e c au se of co ns i de r ab l e va r i a bi li t y in se ns i ti vi t y t o in su l in , t r e at me n t s hou l d c omm e nc e wi t h
s ma l l d os es o f r ap id - o r s h o rt - ac t in g i ns ul i n t o a vo i d i ni t ia l o ve r t r ea tm e nt . E ve n mi ld s y m p to ms
o f h ypo g l yce mi a e a rl y i n t h e c ou r se o f t he r ap y c an f r ig h te n t h e p at i en t a nd f am il y a nd in t e rf e r e
wi t h t h e e f fe c ti ve us e o f i n su li n o ve r t he lo ng t erm . In i ti al do sa g e r e qu i rem e nt s
P . 5 0 -3 4
a r e 0. 2 t o 0 . 3 U /k g p e r da y. Mo s t c hi ld r e n e ve nt ua l l y ne ed 0 .5 to 0 .7 un i ts/ k g /d a y. O nc e t he
D K A h as be e n t r ea t ed wi t h an in su l in in f us io n , b ol u se s o f r e gu l ar in su l in , in s ul in li sp r o , o r
i n su li n a sp a r t c an be adm i ni st e r ed acc o r di ng t o a sl i di ng sc al e . Th e f ol lowi n g d a y, m os t
c h il d re n c an be t re a t ed wi t h a mi xt u r e o f r e gu la r o r r ap id - ac t in g i ns u li n ( li s p ro or as p ar t ) a n d
i n t er m ed ia t e i ns ul i n ( Le nt e o r N P H ) o r l on g -a c ti ng i ns ul in ( in su l in gl a rg ine o r Ul t r al en t e ).
A n a lt e rn a ti ve ap p r oa ch i s to i n t ro d uc e t wi c e -d a ily i n su l in in je c ti on s u si n g N P H o r Le n te .
B a s ed on a d os e o f 0 . 5 U / k g p e r d a y, 6 0 % ca n be g i ven be f o re br e ak f as t a n d 4 0 % b ef o re t he
e ve n i ng m e al . F o r t h os e c h il d re n p r es e nt i ng wi t h m o r e su bs t an t ia l we i gh t lo ss an d ap p re ci a bl e
k e to n u ri a , r eg u la r in su li n, i ns ul i n li s pr o , o r i ns u li n a sp a r t e qu i va le n t t o 0 . 25 U / kg pe r da y ca n
b e ad d ed . Ho we ve r , yo un g e r c hi ld r e n ma y b e q uit e se ns i ti ve to r eg ul a r i ns u li n a nd r eq u i re
e i t he r m in im a l am o un t s o r n on e a t a l l. W he n ve ry l o w d o s es a r e n e ed ed , d i lu t io n o f i ns u li n c an
b e c o ns id e re d to in c re ase t he ac cu r ac y o f m ea sur i n g d os es . Al so , o n e mig h t c on si d e r us e o f
t h e B D Pe n Mi n i t ha t de live r s 0 .5 to 15 un i ts o f ins u li n i n ½ - un i t i nc re me n ts .
C l i ni c al N ot e : J . C. wa s in i t ia ll y t r ea t ed wi t h t wi ce - d a il y H u mu li n 7 0 /3 0 : 6 u n i ts e ve r y m or n in g
a n d 4 un i ts e ac h e ven ing ( 0 .5 U /k g p e r d a y) . Howe ve r , o wi n g t o f r e qu en t h yp o gl yc em ia
o cc u r ri n g a t 9 P M, h e r eve n i n g d os e wa s ch a ng ed t o 4 un i ts N P H a t b e dt im e .
Injection Sites
Ar e t h e r e c om m en d ed si t e s o f i nj e ct i o n d i f fe r en t f o r ch i ld r e n ? D o e s th e ag e o f t h e c hi l d
play a factor?
A l t h ou gh ma n y s t ud i es exi s t i n ad ul t s i n ves ti g at i ng t he r at e o f S C i ns u li n a b so r p ti on de p en d in g
o n th e s i te an d d ep t h o f i n je c ti on , it is n o t c le a r wh e t h e r th es e re su l ts are a pp li ca b le to
c h il d re n . F o r i nf a n ts wi t h a b un d an t S C t is su e , i nje c ti o n si t es ar e us ua ll y p l en t i fu l . F o r so m e
t o d dl e rs wh o ha ve lo st th e i r “ b ab y f a t, ” lo ca t in g a n ap p ro p r ia t e si t e f o r i nj e ct i on c a n b e
d i f fi cu l t. I nj ec t in g i ns ul i n i n to th e ab do me n o f c h ild r e n wi t h mi n im al S C a bd o mi n al fa t o r in ve r y
yo u n g c hi l dr e n ma y n o t b e ad vi sa b le . Ro t a ti on of i nj ec t io n s it e s b et we e n a r ms , th ig h s, an d t h e
u p p er - o ut e r q u ad r an t o f t h e b u t to ck o r hi p a r ea , a s we l l as t he ab d om in al a r e a i n ol d e r
c h il d re n , i s r ec om me n ded . To ac h ie ve c o ns is te n t a bs o r pt i on , i ns u li n i nj ect i o ns c an be
p a t te r n ed ; f o r e xa m p l e, u s in g t h e a rm s f o r t h e mo r n in g i n je ct i on an d t h e th i gh s f o r t h e e ve ni n g
i n je c ti on . U nf o r tu n at e l y, m a n y c hi l d re n a nd t ee ns c on si s te n tl y i nj ec t th ei r i n su li n i n to a s in gl e
a r e a f o r c on ve n ie nc e , acc es si b il i t y, a nd co mf o r t. Th i s r es ul ts in t he de ve lo p me n t o f f a tt y
d e p os it s a nd sc ar t iss u e d u e t o i ns u li n a ct i on at th e lo ca l t is su e l e ve l. I nsu l in ab so r p ti o n f r om
t h es e h yp e r t ro p hi ed a rea s i s g en e r al l y po o r a nd m a y ma ke gl yc em ic c o ntr o l q u it e va ri a bl e .
S p r i ng - lo a de d i nj e ct i on d e vi ce s m a y b e h e lp f ul in r e du ci ng t he c h il d 's f ea r o f n ee d le s a nd
e a si n g ac ce ss to di f fi cu l t - t o - r ea ch in j ec ti o n si t es .
Blood Glucose Monitoring
H ow of t e n s h ou l d J . C . m o n i to r h e r b l o od gl u co s e ?
I m me di a te l y f ol lo wi n g dia g n os is , b lo o d g lu co se de t e rm i na ti o ns s h ou ld be o b t ai ne d fo r J . C .
b e f o re ea ch m e al an d a t b e d ti me . A mi n im um o f th r e e t o f o u r t es ts pe r day wi l l c on s t ru ct a
u s ef u l p r of il e of he r da ily f l u ct u at i on s. A dd i ti o na l t e st s s ho ul d b e p e r fo r me d wh e n e ve r J . C.
e xp e r i e nc e s h yp og l yce mi a or ke t on u ri a o r wh e n sh e be co me s a cu t el y i ll . Th e se ge n er a l
r e c omm e nd a ti on s m us t b e i nd i vid u al i ze d, ho we ve r . F o r e xa m p le , i t m a y no t be ne ce ss a r y fo r a
c h il d t o t e st hi s o r h e r b lo o d g lu c os e l e vel s b ef o re l un ch at sc ho ol i f t he r e a r e n o c u r re n t
p r o bl em s wi t h g lu co se co n t r ol an d p e rf o rm i ng the t es t i s d is r up t i ve o r m ak es t he c h il d f e el
“ d i f fe r en t . ” F o r i n fa n ts , th e ea r lo b es a n d h ee l p r ovi d e al t e rn a ti ve bl oo d s ou r c es fo r
f i n ge r st ic ks . En t hu si as m f o r fr e qu e nt bl o od gl uc os e te st i ng te n ds to wa n e wi t h d u ra t io n o f
d i ab e te s . H o we ve r , f am ili e s wh o a r e i ns t ru ct e d on ma n ag i ng di ab e te s o n t h e b as is o f t es t
r e s ul ts a re be t te r m o ti vat e d to pe rs e ve r e wi t h S MB G .
Honeymoon Period
O ve r t h e n ex t 2 m o nt h s, J . C .' s in s ul i n re q u i rem e n t s d ec r e as e d t o 2 un i t s tw ic e d a i l y. H a s
h e r d ia b e te s g o ne i n to r e m i ss i o n?
A p p r o xi m a te l y 20 % t o 3 0% o f i nd i vi du al s wi t h t ype 1 d i ab e te s g o i nt o a r em is si o n p ha se
( h o ne ym o on pe r io d ) wi t hi n da ys to we e ks of th e i r d i ag no si s . 9 4 Du r i ng th is t im e , wh ic h c an la s t
f o r we e ks to mo n th s, C -p e p ti de ca n b e m ea su r ed , in d ic at i ng a r e tu r n o f p a nc r ea t ic fu nc t io n ;
i n su li n re q ui r em en t s may d i mi n is h p a rt i al l y o r com p le t el y. A s il l us t ra t ed by J . C . , t h is p r es e nt s
c l in ic al l y as m a rk e dl y d ec r e as ed in su li n re q ui r eme n ts t o ma i nt a in no rm o glyc e mi a . Al t ho ug h i t
i s te mp t in g t o d is co n ti n ue i ns ul in , di ab e te s i n va ria b l y r ec ur s . To m in im i ze t h e p os si bi l it y o f
i n du ci n g i ns ul i n a ll e rg y se c on d ar y t o i n te r mi t te n t i n su li n e xp o s u r e a nd to a vo i d e n ge nd e r in g a
s e ns e o f f a ls e h op e i n J .C . t h at he r di se as e h as b e e n cu r ed , m a n y c li n ic ia n s co n ti n ue in su l in
e ve n if t he do se s a r e min u sc ul e . J . C. sh o ul d b e fo l lo we d c lo se l y fo r ri si n g b l oo d g lu c os e
c o nc en t r at i on s.
Hypoglycemia
J . C . ' s p a re n t s c o nt a c ted t h e c l in i c t o r ep o r t tha t J . C . i s h a vi n g n i gh tm a r e s a nd i s
aw ak e ni n g i n th e m i d dle o f th e ni g h t c om p la i ni n g o f a h e ad a ch e a n d s t o m ac h p a in .
H ow e ve r , t h es e s ym p t o m s r es o l ve b y n o o n t h e f o l l ow in g da y. H e r c u rr e n t i ns u li n r eg i me n
i s N P H 4 u n i ts B I D w it h r e g u la r i ns u l in 2 u n i ts b e f o r e b r e ak f as t an d lun c h . Co u l d J . C . b e
e x p e ri e nc i n g n o ct u r n al h yp o g l yc e m i a ? H ow do t h e s ym p t o m s o f h yp o g l yc e m i a d i f f e r i n a
c h i l d c om p a re d w i t h a n a d u l t? H ow c a n t h e ri sk o f h yp o g l yc e m i a b e m i n im i ze d fo r J . C. ?
J . C . ' s p a re n ts a r e a p pr op r i at e l y wo r r i ed . H yp og l yc em i a is a s e ri ou s a nd of t e n l if e - th r e at e ni ng
c om p li ca t io n o f d i ab e te s m a na g em en t i n c hi l dr e n, a n d t he r isk o f h yp og l yce m ia in c re as es wi t h
a t t em p ts t o m ai n t ai n m eti c ul ou s c on t r ol of bl o od g l uc os e l e ve ls . C o mm on c a us es of
h yp o g l yc em i a i nc lu de cha n g es i n m e a l a mo u nt s , l a t e o r sk i pp e d me a ls o r s n ac ks , e xe r c is e o r
u n us u al ac ti vi t y, an d a dm i ni st r a ti on o f e xc e ss i ve i ns u li n . B ec a us e ve r y yo u n g ch il d r en m a y n ot
b e ab le t o i de n ti f y o r e xp r e ss s ym p to ms of h ypo g lyc e mi a , c a re t ak e rs m us t o bs e r ve th e c hi ld
c l os el y a nd i d e nt i f y s ymp t om s o r be ha vi o rs as soc i at e d wi t h a f a ll in g b l ood g lu co se . S ymp t oms
o f h ypo g l yce mi a m a y i ncl u de c ra nk in es s , su d de n c r yi n g, r es tl es s s le ep , o r n i gh tm a r es a s s ee n
in J.C.
I n a s tu d y o f ch i ld r en and a do le sc e nt s wi t h t yp e 1 d ia be t es t re a te d wi t h co n ve n ti o na l i ns ul i n
t h e r ap y, no c tu r na l h yp o gl yc em i a
P . 5 0 -3 5
wa s o b se r ve d i n 4 7% and wa s as ym p to ma t ic i n al m os t 5 0% o f ca se s . 9 5 In a n ac c om pa n yin g
e d i to r ia l , t he co mm on c au s es o f h ypo g l yc em i a we r e r e vie we d , a nd pa r en t s we r e e nc o u ra ge d to
o f f e r sn a cks wh e n b e d tim e g l uc os e c on ce n t ra ti on s fa ll be l o w 1 20 to 16 0 m g / d L , t o t e st in th e
e a r l y m o rn i ng ho u rs wh en i ns ul in le ve ls ma y b e pe a ki n g, to sh i ft th e e ve n in g do se of
i n t er m ed ia t e -a ct i ng in su li n to be d ti me , to a voi d us e o f re g ul a r i ns ul i n a t be d t im e, an d to
c o ns id e r u si ng in s ul in li sp r o i n st e ad of r eg ul a r i ns u li n f o r t h e e ve ni n g mea l in pa r ti cu l a r. 9 6 Th e
f l a t, p ro l on g ed ti me - ac t io n p ro f il e o f i ns ul i n g la rg i ne ma y a ls o b e a s ol u tio n to J. C . ' s
h yp o g l yc em i a.
J . C . ' s p a re n ts s ho u ld be i n st r uc t ed to t es t h e r b loo d gl uc os e a t b e d tim e an d to p ro vi d e a s na ck
i f gl uc os e c on c en t ra t io ns a r e l es s t ha n 13 0 t o 1 50 m g / dL ( 7. 2 to 8. 3 m mol / L ) . Th e y s ho ul d a ls o
t e s t J. C . be t we e n 3 an d 4 A M a n d wh e n e ve r t he y s us pe c t h yp og l yce mi a , wi t h t h e c a vea t th a t
b y t h e t im e t h e y te st , c ou n t e r - r e gu la t o r y ho rm o ne s m a y be d ri vi ng up pl as ma gl uc o se
c o nc en t r at i on s. Tr e a tm en t o f h yp og l yce m i a i s a dd r e ss ed in Q u es ti o n 3 8 .
J . C . w a s sw i tc h e d t o a s i n g le da i l y d o s e o f i nsu l i n g l a r gi n e 6 un i t s e ve r y m o r n i n g a nd h e r
n o c t u r na l s ym p t o m s o f h yp o g l yc e m i a r e s o l ved . H ow e ve r , on a f o l low - u p vi s i t , h e r A 1 C
w a s 7 .9 % ( n o r m a l , 4 % t o 6 %) a n d h e r b l oo d glu c o se co n ce n t r a ti o n s at h o me r a ng e d f r o m
3 4 t o 3 90 m g / d L ( 1 .9 t o 2 1 . 7 m mo l / L) . O n o c ca si o n , J . C . re f u se s to ea t a f t e r he r
p r e b r e ak f as t o r p r e d inn e r i nj e c ti o ns o f re g u lar i n s ul i n , c au s i ng he r pa r e n t s t o fe a r a
h yp o g l yc e m i c r ea c t io n . W h y s h o u l d i n s ul i n l i sp r o o r in s u li n a s pa r t be s ub s t i tu t e d f o r
r e g u l a r i n su l i n b as e d on t h e a f o r em en t i o ne d in f o r m a ti o n ?
Ma n y p a t i e nt s f i nd r ap id -a c ti n g i ns ul in s m o re c o nve n i e nt be ca us e th e y c an b e i nj ec t ed 0 t o 1 5
m i nu t es b e fo r e a me al so t ha t l i t tl e p r ep l an ni n g is in vo l ve d. B ec au s e ch ild r e n o f te n h a ve
e r r a ti c e a ti ng ha b it s , a n a d va n ta g e o f r a pi d -a c ti ng i ns ul in s o ve r re g ul a r i ns u li n i s t ha t th e y ca n
a l so be in je c te d i mm ed i at e l y a ft e r a m e al an d t h e d os e c a n b e t ai lo r e d t o t h e a mo u nt o f
c a r bo h yd ra t e i ng es t ed . Th u s, t he ri sk of po s tm ea l h yp o gl yc em ia an d p a r ent a l a n xi e t y i s
l e ss en e d.
J . C . w a s p r es c r i be d th e f o l l ow in g r eg i me n : I n su l i n g l a r gi n e 6 un i t s i n t h e mo r n i ng a nd
l i s p r o a t b r e ak f a s t a nd d i n n e r a cc o r d in g t o t h e f o l l ow in g a l g o r it h m :

0 . 5 u n it if t he bl oo d g l uco s e is < 15 0 m g/ d L ( 8 .3 m mo l /L )

1 . 0 u n it if t he bl oo d g l uco s e is 15 1 to 22 5 m g/ d L ( 8 . 3 t o 1 2 .5 mm ol / L )

1 . 5 u n it s i f b lo o d g lu co se is >2 2 5 m g/ d L ( 12 . 5 mm o l/ L )
T h e go a l i s to ma i n ta i n J . C . ' s b l oo d gl u co s e b etw ee n 10 0 a n d 2 00 mg /d L ( 5 .5 t o 1 1. 1
m m o l/ L ) . He r p a re n t s w e r e ad vi s e d to p r o vi de J . C . a 3 0 -g ca r b o h yd r a t e s na c k a t 1 0 PM if
h e r b ed t i me gl u c os e w a s <1 5 0 m g/ d L . S h e re tu r n e d to t he cl i n ic 3 d ays l a t e r w i th t he
f o l l ow i ng b lo o d g l uc o se va l u es :
8 AM
Noon
3 PM
6 PM
8 PM
10 PM
Day 1
Lispro
1.0 unit
1.0 unit regular
insulin
Glargine
6.0
units
Glucose
(mg/dL)
159
46
196
292
184
Glucose
(mmol/L)
8.8
2.6
10.9
16.2
10.0
Day 2
Lispro
0.5 unit
0.5 unit
Glargine
6.0
units
Glucose
(mg/dL)
165
215
191
131
142
208
Glucose
(mmol/L)
9.2
11.9
10.6
7.3
7.9
11.5
Day 3
Lispro
0.5 unit
0.5 unit
Glargine
6.0
units
Glucose
(mg/dL)
83
159
147
109
99
193
Glucose
(mmol/L)
4.6
8.8
8.2
6.1
5.5
10.8
Af t e r t h e f i r s t d o se o f 1. 0 u ni t i ns u li n li s p r o, J.C . ' s bl o o d g l uc o se d r op p e d t o 46 mg / d L
( 2 . 6 m m ol / L ) . T ha t e ve ni n g , J . C . 's pa r e n ts g a ve h e r 1 . 0 u n i t r e gu l a r i ns u l i n b ec a us e th e y
f e a r e d h yp o g l yc e m i a se c o nd a r y t o i n s u li n li sp r o . H ow e ve r , h e r 2 - h ou r p o s tp r a n di a l b l oo d
g l u c os e c o nc e n t ra t i on r e m a in e d e l e va te d at 29 2 mg / d L ( 16 . 2 m m ol / L ). T h e f o l low i n g d a y,
a f t e r co n t ac t i ng t he d iab e t e s c li n i c, J . C . ' s p a re n t s w e re i ns t r u ct e d t o d e c re a se t he l is p r o
s l i d in g s c a le b y 0 . 5 u n it a t e ve r y g l u c o s e le ve l. E x p la i n t h es e fi n d in gs .
J . C . i s c le a rl y ve r y s en sit i ve t o in s ul in an d b ec ome s m o re so as b l oo d g luc os e c o nc en t r at io n s
c om e u n de r c o nt r o l. A n e xa g g e r a te d bu t d el a ye d r e sp o ns e t o i ns ul i n l is pro oc cu r r e d o n t he
f i r st da y, wh i c h c au se d th e pa r en t s t o f e ar h ypo gl yc em i a f r om i ns u li n l is p ro a nd th e y s wi tc h ed
b a ck to r eg ul a r i ns ul i n be f o r e d in ne r . B y de c re asi n g t h e i ns ul in li sp r o b y 0 . 5 u n it , go od
c o ve r ag e i s p r o v id ed f or h e r m e al s wh i l e t h e i ns uli n gl a rg i ne pr o vi de s b asa l in su li n .
F u r t he r mo r e, J. C . ' s p a ren t s a r e l es s a n xi o us be ca u se th e y a re ab l e t o i nje c t h e r l is p ro do se s
j u st a ft e r J . C . h as e a te n a n d a dj u st th e d o se ba se d on th e g r am s o f c a rbo h yd r a te J . C .
c o ns um es .
Using Insulin in Special Situations
Insulin Stability: Factors Altering Control
T . M ., a 3 1 - ye a r - o l d f a rm e r , ha s h a d t yp e 1 d i ab e t e s f o r 2 0 ye a r s . H e h a s b e en r e la t i ve l y
w e ll c on t r o l le d o n hi s cu r r e n t r eg i me n o f s pl i t -m i x ed d os es o f re g u la r a n d N P H h u ma n
i n s u li n fo r s om e ti m e. D u r i n g t he w i n te r an d sp r i n g s e as o ns , hi s bl o od g l uc o se
c o n ce n t r a ti o ns h a ve ran g e d f r o m 9 0 to 14 0 m g/ d L , a n d t h e A 1 C me a sur e d a t h i s l as t cl i n ic
vi s i t 3 m o n t hs ag o w as 7 . 5 %. I t i s n ow Au g u s t. F o r t he pa s t 2 mo n t hs , T . M. h as no t i ce d
t h a t hi s di a be t es i s n o t u n d e r g o od c on t r o l. H is b l oo d gl u co s e c o nc en t r a t i on s va r y w id e l y
f r o m co n ce n t r a ti o n s a s l ow a s 6 0 m g/ d L (3 . 3 mm o l / L) t o a s h i g h a s 2 40 m g/ d L (1 3 .3
m m o l/ L ) . He ha s no ex pl a n a ti o n fo r t hi s . O n i ns p e c ti o n , h is vi a l o f r eg u l a r i n s ul i n i s
c l o u d y a n d a w h i te p r ec i p i ta t e i s c l i ng i n g t o th e N P H vi a l , g i vi n g i t a f r o s t e d a pp e a ra n ce .
B o t h vi a l s a r e a p p ro x im a t e l y o n e - t h i r d f ul l . Wh a t f ac t o r s m a y b e c o nt r i b u t i ng t o T .M . ' s
p o o r g l yc e m i c c on t r o l ?
[ S I un i ts : b l oo d g lu c os e c o nc en t r at i on s, 5 .0 to 7.8 mm ol / L ; A 1 C , 0 . 08 5 ( n or m a l, 0. 0 4 t o 0 . 06 ) ]
Ma n y f a c t o rs m a y b e co nt r i bu t in g to T. M. ' s p o o r co n t r ol . Th es e a r e d isc uss e d i n t he
s u bs eq u en t s ec t io ns .
Physical Changes
B o t h o f T. M. ' s i n su li n vial s h a ve c h an ge d i n a p pea r a nc e . T. M. s h o u ld be in s t ru c te d n o t t o us e
h i s r e gu la r in su li n i f it is d is co l o re d ; h as b ec om e c lo u d y o r th ic k en ed ; or c o nt a in s sm al l ,
t h r e ad li ke o r o th e r s ol i d p a r ti cl e s. As di sc us se d in
P . 5 0 -3 6
Q u e s ti o n 1 3 , th e c lo u di ne ss ma y b e c au se d b y co n t am in a t i on o f r e gu la r in s ul in wi t h N P H . I f
T. M. r e u s es h is s yri n ge s, t hi s a ls o m a y be c a us ed b y t he s i li co ne oi l th a t i s u se d to c o at
n e e dl es of di sp os a bl e s yr i n ge s . 9 7 Th e si li c on e o il ca n d e na t u re th e i ns u lin , r ed uc i ng it s
p h a rm ac ol o gi c e f fe ct .
Flocculation
P u r i fi e d p o rk o r hu ma n N P H c a n so me t im es fl occ u la t e o r c r ys t a ll i ze o n to t h e i ns ul i n b ot t le . 98
Th i s r es ul ts in a s ig n i f ica n t l os s o f p o te nc y, wi t h i ns u li n c on ce n t ra t io ns in t he r em ai n in g
s us p en si o ns va r yin g fr om 6 t o 6 4 U /m L ( la b el e d 1 0 0 U/ m L) . Th is ph e no me n o n ca n o cc u r
p r e ci pi t ou sl y, g en e ra l l y a f t e r 3 to 6 we e k s o f us e. I nc o rp o r at i on of ad d it i on a l zin c i nt o th es e
p r e pa r a ti o ns d u ri n g t he m a nu f ac tu r i ng p ro ce ss ha s m in im i ze d t hi s p r ob l em . N e ve rt h el es s, al l
p a t ie n ts s ho u ld be wa r ne d to in sp ec t th e ir vi al s c a r ef u ll y b ef o re ea c h i nje c ti o n a nd to di sc a rd
o r e xc h a ng e t h em i f th e y h a ve c r ys ta l li ze d ( F ig . 50 - 7 ) .
Temperature
I n su l in is a f ra g il e m ol ecu l e t h at ca n b e d am a ge d b y t em p e ra t ur e e xt r e m es . Al t ho u gh al l
c om me r ci a ll y a va il ab l e in s ul in s a r e s ta b le fo r at l e as t 1 mo n th at r oo m t em p e ra t ur e (6 8 ° t o
7 5 ° F ) , ma n uf ac t u re r s r eco mm e nd th a t i ns ul i n b e re f r ig e r at e d a nd th e A D A r e c omm e nd s
a vo i di n g t em p er a tu r e e xt r e m es (3 6 ° o r 8 6 ° F ). 6 9 In p r ac ti ce , m os t p a ti e nt s s t or e via ls cu r r en t l y
i n us e a t r o om te mp e ra tu r e be ca us e i nj e ct io n o f c o ld in su li n i s u nc om f o rta b le . Th e Un i te d
S t a t es Ph a r mac o pe i a ( US P ) r ec o mm en ds th a t p at i e nt s d is ca r d vi a ls th a t h a ve no t b e en
c om p le t el y us e d i n 1 m on t h i f th e y ha ve be e n kep t a t r oo m t em p e ra t ur e .
Th e s t ab il i t y o f in su li n a t t e mp e ra t u re s o f 7 5 ° t o 1 0 0 ° F is un kn o wn , bu t all i ns ul in s l os e
s i gn i fi ca n t p ot e nc y wi t h in 1 to 2 mo n th s a t 1 0 0° F. T. M. l i ve s i n a n a re a wh e r e t em p er a t ur es
f r e q ue n tl y e xc e e d 1 00 ° F d u ri n g t h e su mm e r mo n th s . Th er e fo r e , i t i s im p ort a n t t h at he no t s t o re
h i s i ns ul in in an au t om obi l e o r i n th e s un , wh e r e it m a y b e s ub j ec t t o d e te ri o r at i on . It al so is of
i n t er e st th a t m an y wh o l es a le d ru g d is t ri b ut o rs and so me ma il o rd e r p h ar ma c ie s d o n ot t ak e
s p ec ia l p ac ka g in g p r ec au t i on s wh e n de l i ve ri ng ins u li ns to ph a rm ac i es d u ri n g t h e su mm e r
m o nt hs . Th us , i n ad ve r t en t e xp o s ur e to hi gh t em pe r a t ur es d ur i ng th es e mo n t hs m a y al t e r t he
p o t en c y an d a ct i on s o f in s ul in s . F r ee zi n g a pp a ren t l y do es no t af f ec t t h e po t e nc y o f i ns ul in , bu t
m a y ca us e a g gr e ga t io n o f t he pr ec i pi t at e . T h is co u ld al t e r t h e a bs or p ti o n k in e ti cs of th e
p r e pa r a ti o n. 9 9
FIGURE 50-7 Insulin vial with crystallized insulin
(photograph). (Used with permission from reference 298.)
View Figure
Other Factors Altering Response to Insulin
Ma n y o t h e r f ac to r s ma y b e al t e ri ng T. M. ' s r e s po ns e to in su li n . Th e h ea t i n t h e s umm e r m on t hs
m a y in c re as e c i rc ul a ti o n t o t he i n je c te d s it e , t hu s i n c re as in g th e o ns e t a nd s ho r t en i ng th e
d u r a ti on o f ac t io n o f h is i n su li n . E xe r ci s e o f t he in j ec t ed li mb m a y a f f ec t in s ul in ac t io n
s im i la r l y. Du r in g th e s umm e r m on t hs , f a rm e rs t ypic a ll y a r e mo r e p h ysi ca l l y a c ti ve an d , as a
c o ns eq u en ce , re q ui r e l es s i ns ul i n t ha n u su a l. O th e r fa ct o rs t ha t c an al t e r i ns u li n a ct i on a re
l i st e d i n Ta b l es 5 0 -1 2 and 5 0 -2 0 .
W hen p at i en ts li ke T. M. o b se r ve th a t t h ei r i ns u li n s ee ms to wo r k le ss we l l e ve n wh e n t h e
p r o du c t is we l l wi t hi n th e e xp i r a t i on da t e a nd th e re a r e n o o b vio us ph ys ic al ch a ng es , we
r e c omm e nd th a t t h e y i n je c t i ns ul i n f r om a f re s h vi a l t o a ss es s wh e t h e r i nsu l in f ro m t h e o ri g in a l
vi a l ha s d et e r io r at e d. I f th e r es po ns e re ma in s t h e s am e , t he y s ho ul d wo r k wi t h a cl in ic i an to
i d en t i f y o t he r r ea so ns for t h ei r de cr e as ed r es po ns i ve ne ss to in su li n .
Exercise and Insulin Requirements
J . S . is a 1 7 - ye a r - o l d , no n o b es e , p a ti e n t w i t h typ e 1 d i a b e te s w ho w as d i ag n os e d a t a g e
1 2 . He c u r re n t l y i s m o de r a t e l y w e ll c on t r o l le d o n a s i ng l e d a il y d o s e o f L an t u s 1 8 u n i ts a t
b e d t im e w i th 4 t o 6 u n its o f in s ul i n as pa r t w i t h m e a ls ( de p en d i ng o n ca r b o h yd r a t e i n t a k e) .
H i s A 1 C i s 7. 8 %, a n d his b l oo d gl u co s e l e ve ls b e f o r e m ea l s ra n ge f r om 1 50 t o 1 90 mg / d L
( 8 . 3 to 10 . 5 m mo l / L ). Fas t i n g b l oo d gl u c os e c on c e n t ra t i on s in t he c li ni c r a ng e f ro m 1 3 0 t o
1 7 0 m g /d L (7 . 2 to 9. 4 mm o l / L) . H e h as r a r e h yp o g l yc e m i c r e a c t io n s t ha t a r e a ss o ci a t ed
w i t h s ki p p ed me a ls , a nd h e g e ne r a l l y i s c o m p li a n t w i th h is p r es c r ib ed m ea l pl a n. J . S.
w o ul d li k e t o be g in a j og g i n g p r o g ra m . W h a t e ff e c t is jo g g in g li k el y t o h a ve o n h is
d i a be t i c c o n t ro l ? W h a t p r e c au t i o ns , i f an y, s h o u l d h e ta k e?
[ S I un i t : A 1 C , 0 . 10 ]
E xe r c i s e h as va r yi ng ef fe c ts on pl as ma gl uc os e le ve l s i n p at i en ts , s uc h as J. S . , wh o a r e t ak i ng
i n su li n . I n t h e r es t in g s t at e , m us cl e d e ri ve s a p pr oxi m a t e l y 10 % o f it s me t ab o li c r e qu i re m en t
f r o m g lu co se . In c o nt r as t, a lm os t a ll o f t he mu sc le ' s m e ta b ol ic r eq ui r e m en t s a r e d e ri ve d f r om
g l uc os e d u ri n g mo d e ra t e t o he a vy e xe r c is e . Mu scl e gl yc og e n st o r es a r e de p le t ed q ui te r ap i dl y,
a f t e r wh i c h g lu co se is der i ve d f ro m t he pe r ip h e ra l c i rc ul a ti o n. To me e t t he i nc r e as ed gl uc os e
d e ma n ds , h ep a ti c g l yco ge n ol ys is an d g l uc on e og en e si s i nc r ea se . Th is i s me d ia t ed p ri ma r il y
t h r o ug h s up p re ss io n o f in s ul in se c re t io n a nd in c re a se d s ec r et i on of co u nte r - r e gu la t o r y
h o r mo ne s s uc h a s g lu cag o n . L o w, p er mi ss i ve l e ve l s o f i ns ul i n a r e r eq u i red f o r g lu co se
u t i li za t io n b y t he mu sc le . I n no nd i ab e t i c i nd i vid u al s , h ep a ti c g lu co se o ut pu t an d p e r ip he r a l
u t i li za t io n a r e b al a nc ed s uc h th a t e ug l yce mi a i s m a in t ai ne d d u r in g e xe r c is e . 1 0 0 , 1 01
I n a p a ti en t l ik e J . S . , e xe r c is e ma y c au se h ype r gl yc em i a o r h yp o gl yc em ia i f h e d o es no t t a ke
p r o pe r p re ca u ti o ns . I f h e i s i ns ul i n d ef ic i en t wh e n h e c om me nc es e xe r c is e, h ep a ti c g lu co se
o u t pu t wi l l b e i nc r ea se d , b u t p e ri p he r al u t i li za t ion wi l l be de c re as e d a nd h yp e r gl yc em i a wi l l
e n su e . Th u s , p at i en ts li ke J . S. wi t h t ype 1 d ia b ete s s ho u ld no t e xe r c i se i f t h ei r bl oo d gl uc os e
c o nc en t r at i on s e xc e e d 25 0 an d t h e y h a ve k e to si s o r if le ve ls e xc e e d 3 00 m g /d L ( wi t h o r
wi t h o u t k e to si s ), be c a use t he se le ve ls us u al l y i nd i ca t e i ns ul in de f ic ie n c y. 1 0 1
P . 5 0 -3 7
C o n ve r se l y, e xc e s s i ns uli n wi l l e nh a nc e p e ri p he ra l ut i li za ti o n o f g lu c os e b y m us cl e a n d
s u pp r es s h ep a ti c g lu co se o ut p ut . B ot h c an co n tr ib u t e t o h yp og l yc em ia . Hyp o g l yce mi a i s m or e
l i ke l y to oc cu r i n p a ti e nts wh o s e b lo od gl uc o se co n ce n t ra t io ns a re no rm a l o r lo w j u st be f o re
e xe r c i s e. Th u s, if J. S . ' s b l oo d g l uc os e c on ce n t rat i o n is no r ma l o r l o w ( < 10 0 m g /d L ) b e fo r e h e
b e gi n s e xe r c is e , h e sh o ul d ea t a ca r bo h yd r at e s na ck ( 10 t o 2 0 g ) a nd ha ve a dd i ti on a l
c a r bo h yd ra t es r ea di l y a va i la b le du r in g a n d a f te r e xe r c i s e. 1 01 H e s ho ul d d e la y h is do se of
l i sp r o u n ti l a f te r e xe r c i sin g an d a d ju st th e a m ou nt a cc o rd in g t o hi s p os te xe r c is e b lo od gl uc o se
l e ve l .
I t is le ss we l l a pp r ec i at ed t ha t pe r ip h er a l g lu co se u t il i za ti o n r em ai ns hi g h a f t e r e xe r c is e h as
b e e n di sc o nt i nu ed . Th is i s th ou g ht t o b e r el a te d to t he r ep l en is hm en t of glyc o g en st o re s i n t h e
l i ve r a n d m usc l e. Th u s, if a pp r o pr i at e a d ju st me n ts a re no t m a de i n di et and i ns ul in do s e a ft e r
e xe r c i s e, h ypo g l yce mi a c a n oc c ur 10 t o 1 2 h ou r s t h e re a ft e r . 1 0 2
F o r pa t ie n ts wh o i n je c t in s ul in in t o t h ei r th ig hs , jo g gi n g m a y e n ha nc e i nsu l in ab so r p ti o n. Th e
a b so r p ti on o f r eg u la r in su l in is in cr e as ed wh e n i t i s a dm i ni st e r ed ju st be f or e e xe r c is e ( wi t hi n 5
m i nu t es ) , b ut i t d oe s n ot a p pe a r t o b e a f f ec te d i f i n je c te d 3 0 t o 4 0 m in u tes be f o re e xe r c is e.
A b s o rp ti o n o f t h e i nt e rme d ia t e -a c ti ng o r l on g -a c ti n g i ns ul i ns i s l es s l ik el y t o be au gm en t ed b y
e xe r c i s e. 1 03 S om e h a ve s ug g es t ed th a t i ns ul in be i n j ec t ed at a s it e t h at is no t e xe r c is ed , f o r
e xa m p l e , t he ab d om en , to mi n im i ze t hi s e f fe ct .
I n su mm a r y, J . S. s h ou l d b e en co u ra g ed t o b eg in a n e xe r c is e p r og r am . He s ho u ld te s t h is b l oo d
g l uc os e c on ce n t ra t io ns be f o r e, du r in g , a nd a ft e r e xe r c i s e a nd ad j us t h is in s ul in do s es a n d f oo d
i n t ak e ac c or d in gl y. I n g en e r al , e xe r ci s e sh o ul d be a vo id e d a t t im es c o r res p on d in g t o p e ak
i n su li n a c ti on , be ca us e hi g h l e vel s c an s u pp r es s c o un t e r - r e gu la t o r y ho r mo n es th a t s ti mu l at e
h e p at ic gl uc os e p r o du ct io n ( Ta bl e 50 - 23 ) . Re g ula r e xe r c is e m a y i n cr e ase t is su e s en si t i vit y t o
i n su li n a n d e ve n tu al l y lowe r J . S . ' s i ns ul i n r e qu i rem e nt s . V i go r ou s e xe r c ise is co n tr a in d ic at e d
i n pa t ie n ts wi t h r e ti n al o r vi t r e ou s h em o r rh ag e s be c au se r et i na l d e ta ch men t ma y oc cu r .
Table 50-23 Exercise in Patients With Diabetes
1. Test blood glucose concentrations before, during, and after exercise.
2. For moderate exercise (e.g., bicycling or jogging for 30–45 min), ↓ the preceding
dose of regular insulin by 30–50%. If glucose concentration is normal or low before
exercise, supplement the diet with a snack containing 10–15 g of carbohydrate.
3. To avoid ↑ absorption of regular insulin by exercise, inject into the abdomen or
exercise 30 min–1 hr after injection.
4. Individuals with low glycogen stores may be predisposed to the hypoglycemic
effects of exercise. Examples include alcoholics, fasted individuals, or patients on
extremely hypocaloric (<800 calories), low-carbohydrate (<10 g/day) diets.
5. Patients taking insulin are more susceptible to hypoglycemia than those taking
sulfonylureas. Patients with type 2 diabetes mellitus treated with diet are unlikely to
develop hypoglycemia.
6. Watch for postexercise hypoglycemia. Individuals who have been exercising during
the day (e.g., skiing) should ↑ their carbohydrate intake and test their blood glucose
concentration during the night to detect nocturnal hypoglycemia. Hypoglycemia can
occur 8–15 after exercise.
7. If the glucose concentration is >240–300 mg/dL, the patient should not exercise.
This indicates severe insulin deficiency. These patients are predisposed to
hyperglycemia secondary to exercise.
8. Patients with severe proliferative retinopathy or retinal hemorrhage should avoid
jarring exercise or exercise that involves moving the head below the waist.
I n ob es e i n di vi d ua ls wi t h t yp e 2 d ia be t es m e ll i tu s wh o a r e tr e at e d wi t h di et , e xe r c is e i s u nl ik el y
t o ca us e h yp o gl yc em ia . A n e xt r e m el y l o w - c al o ri e d i et ( <8 0 0 ca l o ri es ) th a t a ls o i s l o w i n
c a r bo h yd ra t es m a y de c re a se an in d i vid ua l ' s e xe r c is e e n du r an c e b ec au se m us cl e g l yc og en
s t o re s a r e n ot ma in t ai n ed . 1 00 P at i en ts wi t h t ype 2 d ia be t es wh o a re t re a te d wi t h i ns u li n
s ec r e ta g og u es o r in su li n m a y be co me h ypo g l yc em ic if in s ul in le ve ls a re h i gh en o ug h to
i n c re as e p e ri p he r al ut i li za t i on of gl uc os e a n d s upp r e ss h e pa t ic g l uc os e o ut p u t . Th u s, pa t ie n ts
wi t h t yp e 2 d ia be t es wh o a r e n o rm og l yc em ic b e for e e xe r c is e a ls o s ho u ld co n si d er in c re as i ng
t h e ir ca r bo h yd r at e i n ta ke. 1 0 4 B ec a us e p at i en t s wi t h t yp e 2 d ia be t es do not h a ve a n a bs ol u t e
l a ck o f in su li n , t h e y a r e le ss li ke l y t o b ec om e h ype r g l yce mi c i n r es p on se to e xe r c is e .
Sick Day Management
R . D . , a 3 2 - ye a r - o l d w om a n w i th t yp e 1 d i a b e te s , ha s b e en w e ll c on t ro l l e d o n t h r e e d ai l y
d o s es o f i n su l i n f o r th e p a s t 6 m o n th s . How e ve r , 2 d a ys a g o , s h e b ega n t o d e ve l op si g n s
a n d s ym p t o m s co n s is t en t w i t h th e fl u . T h i s h as m ad e h e r an o r ex i c a nd n a us ea t e d a n d
n ow s he h as be g u n t o vo m i t ; c o n s eq u en t l y, h e r f o o d i n ta k e h as be e n m i n im a l. B ec a us e
R . D . i s n o t e a t in g a t t his t i me , s h o ul d s h e d i sco n t i n ue he r i ns u l in ?
I n su l in r eq ui r em e nt s a l wa ys in c re as e i n th e p r ese n ce of an in f ec t io n o r ac u te il l ne ss , e ve n i f
t h e fo od in t ak e i s d im in is h ed . Pa t ie n ts wi t h t yp e 1 d ia be t es , s uc h a s R . D ., c omm o nl y d ec r ea se
o r el im i na t e i ns ul i n d os es un d e r t he se ci rc u ms tan c es , a n d i t is in ju st t his se t ti n g t ha t
k e to ac i do si s o cc u rs .
Th e r e f o re , R . D . sh o ul d be i ns t ru ct e d t o m ai n ta in h e r us ua l d os e o f i ns u li n a n d t es t h e r b lo o d
g l uc os e c on ce n t ra t io n e ve r y 3 to 4 h o ur s ; t he la t te r is pa r t ic ul a rl y im p o rt an t if sh e h as be co me
n o n ad he r e nt wi t h he r b l oo d gl uc os e t e st in g . I f bl oo d gl uc os e c on ce n t ra t ion s a r e a b o ve t he
u s ua l ra ng e , s up pl e me n ta l do se s o f r e gu l ar o r i ns u li n l is p ro o r i ns ul in asp a r t s ho u ld be
a d mi ni s te r ed ac co r di n g to a p r es c ri b ed al go r i th m b a se d o n h e r s en si t i vit y f a c to r . R. D . al so
s h ou l d b e i ns t ru ct e d t o te s t h e r u r in e f o r k et o ne s i f h e r b l oo d g lu c os e co nc e nt r a ti o n is ≥ 30 0
m g /d L . Sh e s ho ul d c al l he r p h ys ic i an if he r bl oo d g l uc os e c on ce n t ra t io n rem a in s > 30 0 m g /d L
a f t e r t h re e s up p le me n ta l i ns u li n d os es o r i f sh e be g in s t o d e ve lo p s ig ns an d s ym p to ms re l at e d
t o ke t oa ci do si s (p ol yu r i a, p ol yd i ps ia , d e h yd ra t io n, k et o nu r ia , a n d a f ru it y b r e a th ) . ( A ls o , s ee
Q u e s ti o n 4 0 . ) R . D . a ls o s h ou l d a tt em p t t o m ai n tai n he r fl ui d , m in e ra l , a nd c a rb o h yd ra t e i nt ak e
wi t h e as i l y d i ge st e d f o od a n d f lu i ds ( Ta bl e 5 0 -2 4 ). 1 0 5
Insulin Requirements in Renal Failure
M . B . , a 32 - ye a r - o l d w om a n , h as h ad t yp e 1 d i a b e t es f o r 1 5 ye a r s . O ve r t h e p a st 2 ye a r s , a
g r a d u al de t e r i o ra t i on of h e r r en a l f u nc t i o n —a s r e f l ec t e d b y i n c r e a se d p r o t e in u r i a, se r u m
c r e a t in i n e ( S r C r ) , a n d bl o o d u r e a n i t r o ge n ( B UN ) va l u e s —h a s b ee n obs e r ve d . Wh a t a r e
t h e an t i ci p a te d e f f ec t s o f d ec r e as e d re n al f unc t i o n o n M . B .' s in s ul i n r e q u i r em e n ts ?
Th e e f f ec ts of r en al f ai lur e o n i ns ul in r eq ui r em e nts a re co mp le x a n d , un der va r i ou s
c i rc um s ta nc es , i ns u li n r eq u i re me n ts m a y in c re as e o r de c re as e . Th e ki dn e y i s t h e mo st
P . 5 0 -3 8
i m po r t an t s it e o f e xt r a h ep a t ic i ns u li n m et a bo li sm a n d e xc r e t i on . Re n al c l ea r a nc e o f i ns u li n i s
1 9 0 t o 2 7 0 mL / mi nu t e , ap p r o xi m a te l y t wo - t hi r ds o f he p at ic cl ea r a nc e ( 3 20 t o 4 00 mL /m i nu t e) .
I n no n di a be ti c i n di vi du a ls , th e l i ve r e xt r a c ts a pp ro xi m a t e l y 4 0 % t o 5 0% o f i ns u li n s ec r et e d
e n d og en o us l y b e f or e i t re a ch es t he pe r ip h er a l ci rc u la t io n . 4 7 , 1 0 6 B ec a us e e xo g e n o us i ns u li n i s
d e li ve r e d d ir e ct l y to t he p e r ip h e r y, t he ki dn e ys p la y a mo r e im p o rt a nt r ol e i n i ts el im i na t io n .
I n su l in is fi lt e r ed b y th e g l om e ru l us a n d r e ab so r be d in th e p r o xi m a l t ub u les , wh e r e i t i s
d e st r o ye d e n zym at ic a ll y. Th e k id ne y a ls o c le a rs in s ul in f r om t h e p e ri t ub ula r ci r c u la t io n . 5 1 , 10 7
A t t ha t s i te , i n su li n c an e n h an ce th e re a bs or p ti on o f s od iu m , wh i c h ma y a cc o un t fo r th e e d em a
o cc a si on a ll y o bs e r ved fol l o wi n g t he in i ti a ti o n o f in s ul in t he r ap y i n s om e in d i vid u al s.
Table 50-24 Sick Day Management
1. Continue taking your basic dose of insulin even if you are not eating well or have
nausea or vomiting.
2. Test your blood glucose more frequently: every 3–4 hr.
3. If indicated, give yourself supplemental doses of lisproaspart or regular insulin: for
example, 1–2 U for every 30–50 mg/dL over an agreed-upon target glucose
concentration (e.g., 150 mg/dL). Supplemental doses must be individualized based
on the patient's sensitivity to insulin (see Table 50-14).
4. Begin testing your urine for ketones, especially when glucose readings exceed 300
mg/dL.
5. Try to drink plenty of fluid (½ cup/hr for adults) and maintain your caloric intake
(50 g carbohydrate Q 4 hr). Foods such as gelatin, noncarbonated soft drinks,
crackers, soup, and soda may be used.
6. Call a physician if your blood glucose concentration remains >300 mg/dL or your
urine ketones remain high after two or three supplemental doses of insulin.
D i m in is h ed re n al fu nc t ion ca n b e a cc om p an ie d by d e c re as e d cl e a ra nc e of e nd o ge n ou s a nd
e xo g e n o us in su li n , r e su lti n g i n i nc r ea se d p l asm a c o nc en t r at i on s o f i ns ul i n. Th e r e fo r e , M. B . ' s
i n su li n re q ui r em en t s may d i mi n is h as he r r en al di s ea se p ro g re ss es . Pa t ien t s wi t h mo d e ra t e
d e g re es o f r e na l f ai l u re (g l om e ru l a r f il t ra t io n ra t e [ G F R ] > 22 . 5 mL / mi nu t e ) r e m o ve 3 9% of
i n su li n fr om a r te r ia l p la sm a , s im il a r t o n o rm al s ub j ec ts . In co n tr as t , p a ti en t s wi t h se ve r e re n al
i n su f fi ci e nc y ( G F R <6 mL / mi n ut e ) h a ve a ma rk e d r e d uc ti o n i n i ns ul in r emo va l f ro m a r te r ia l
p l as ma ( 9% ) . 1 0 8 D e c re as e d i ns ul in cl e ar a nc e i n c o nj u nc ti o n wi t h th e an or e xi a , n a us ea , a n d
d e c re as e d f oo d i n ta ke as so ci a te d wi t h u r em ia can l ea d t o h yp o gl yc em ia in su ch in d i vid u al s. In
s om e p a ti e nt s wi t h d ia b et e s , p ar t ic ul a r l y t h os e wit h r es id u al en do g en o us in s ul in se c re t io n
( t yp e 2 ), gl uc os e to le r a nc e m a y no r ma li ze as r ena l fu nc t io n d im i ni sh es , e li m in a ti ng t he ne ed
f o r in su li n .
I n co n tr a st , s e ve re u re mia is as so ci a te d wi t h g lu co s e i nt o le r an ce . Th is app e a rs to be r el a te d t o
t i ss ue r es is t an ce to in su li n s ec o nd a r y to an un k no wn f a c to r th a t c an be rem o ve d b y di a l ysi s.
O t h e r fa ct o rs t ha t m a y alt e r bl o od gl uc os e c on t r ol i n p a ti e nt s wi t h r en a l f ail u r e i nc lu d e d ia l ysi s
a g ai n st gl uc os e -c o nt a in in g di al ys a te s a nd hi g h - do s e g lu co co r t ic oi ds in pat i e nt s wh o h a ve
u n d er g on e re na l tr a ns pla n t a t i on .
A s M. B . ' s r e na l f ai l u re p ro g r es se s t h ro u gh va r io us st a ge s o f s e ve ri t y, m an y a l te r a ti o ns i n h e r
i n su li n d os e s h ou ld be an t ic i pa t ed . Du r i ng th is tim e , M. B . sh ou l d mo n it o r h e r b l oo d g lu co se
c o nc en t r at i on s cl os e l y an d ad ju s t h e r i ns ul in ac co r d in g to an a l go r i th m ( se e Ta b le 50 - 22 ) .
Traveling With Diabetes
J . R . is a 4 2 - ye a r - o l d w om a n w i th t yp e 1 d i a b e te s me l l it u s w ho ha s ju st t a ke n a p os i t i on
t h a t r eq u i r es ex t e ns i ve o ve r s e as a i r t r a ve l . S he i s c o nc e r ne d a b o u t po t e n t ia l p ro b le m s
s h e m a y e n c o u n t e r man a g i ng he r d ia b e te s u nd e r t he s e c i r cu m st a nc es . W ha t a re so m e
b a s ic t r a ve l t i p s J . R . sh o u l d c o ns i de r ?
J . R . ' s p r ed ep a r tu r e p r epa r a ti o ns de pe n d o n t h e du r a ti o n a nd de s ti na t io n of h e r t r ip . Th e
f o l lo wi n g s ec t io ns di sc uss ba si c c on si d er a ti o ns for d ia b e ti cs wh e n t r a vel i ng .
Supplies
J . R . s ho u ld c a r r y a p le n ti f u l b ack - u p su p pl y o f i ns u li n , s yr in g es , b lo o d - t es t in g s up p li es
( i n cl ud i ng an e xt r a ba t ter y f o r he r m e te r ) , a n d g lu c os e t a bl et s . S h e sh o uld d ou bl e he r
a n t ic ip a te d i ns ul i n n ee ds i n c as e o f l os s , d es t ru cti o n , o r u n a vai la b il i t y o f co m pa r ab l e p r od uc ts
i n fo r ei g n c ou n tr i es . F o r e xa m p l e , o nl y U - 4 0 i ns uli n is a va i la bl e i n s om e pa r t s o f t h e wo r l d .
J . R . ' s i ns ul in su p pl y sh ou l d b e i ns ul a te d an d s epa r a t ed in va ri o us b a gs sh e wi l l c a rr y wi t h h e r.
Mo s t s o u rc es a d vis e a g ai n st ca r r yi ng in su li n i n ch e ck ed lu g ga ge , be ca use i ts ef f ec ti ve n es s
m i gh t b e a l te r e d b y x - r a y s ca nn i ng o r b y f re e zi ng t h a t c ou ld oc cu r in th e un p r es su r i zed
b a g ga ge co mp a r tm en t . J. R . sh o ul d t ak e wi t h h e r a b ri e f m ed ic a l hi s to r y an d a p r esc r i pt io n fo r
i n su li n fo r e m er g en c y s i tu a t io ns .
Identification
J . R . s ho u ld c a r r y s o me id e n ti f ic at i on , wh ic h a l e rts me di ca l p e rs o nn el o r ot h e rs to he r di a gn os is
i n em e rg en c y s i tu a ti o ns . Th i s c a n t ak e t h e f o rm of a wa l le t c a rd o r a m e dic a l a le r t b r ac el e t . I n
c e r ta i n si t ua t io ns , s h e sh o ul d c o ns id e r i nf o rm i ng k e y in di vi d ua ls of he r dia b e ti c co n di t io n (e . g. ,
a i r li n e p er so n ne l , h o te l m a na g er s , t ou r gu i de s, tr a ve l in g c om pa n io ns ) . Sh e s h ou l d r e vie w h e r
i n su r an ce po l ic y ca r e fu lly s o th a t s he k n o ws ho w t o ob t ai n c ar e o u t o f th e c ou n t r y an d b r in g
a l on g h e r p o li c y a n d cl a im f or ms . F i na l l y, s h e s ho u ld p ro vi d e f r ie n ds o r re l a ti ve s wi t h a
d e t ai le d i t in e r ar y s o t ha t m ed ic a l ca r e c an be sum mo n ed p ro mp t l y i f d i f fic u lt i es a r e
e n co u nt e re d .
Foot Care
S h o es th a t a r e b r ok en in a n d f it we l l ar e k e y if J.R . a n ti ci pa t es wa l ki n g o r s t an di n g f o r l on g
p e r io ds . N e w s ho es s h ou l d n o t b e wo r n l on ge r th a n 1 ho u r t o p r e ve nt bl is t e rs .
Meal Planning
J . R . s ho u ld t r y to m a in t ai n s om e re g ul a ri t y in he r d i et ( ti me an d a mo u nt s ). W hen i t is t h e
c us t om to t ak e t he e ven in g m e al la t e r t ha n i s us ua l in th e Un i te d St a t es , a l a te af t e rn o on o r
e a r l y e ven in g s n ack sh ou l d b e p la n ne d . To p r e ven t h ypo g l yce mi a , J. R . s ho u ld in f o rm ai r li ne
e m pl o ye es re g ar d in g t h e i mp o r ta nc e o f s e r vin g he r me a l o n t im e. To a vo id u nf o r es ee n e ve n ts
( e . g ., t ra ve l d e la ys ) , J . R. s ho ul d c a r r y s u ff ic i en t fo o d a n d sn ac ks wi t h h e r o n th e p l an e a n d
c o ns id e r u si ng in s ul in li sp r o or as p ar t as t h e p r and i al in su l in if sh e i s us i ng i nt e ns i ve t he r a p y.
Th e r a pi d on se t o f th es e i ns u li ns wi l l g i ve h e r m or e f le xi b i l it y i n a dm in is t er i n g t h e in s ul in wh e n
s h e is ce r t ai n t h e me a l wi l l b e s er ve d . An t ic ip a ti ng t he li ke l y co mp os i ti on o f he r di e t i n a
f o r ei g n c ou n tr y a ls o wi ll h e lp he r de si g n a d i et t ha t ma in t ai ns he r pa t te r n o f ca r bo h yd r at e a n d
c a lo r ic i n t ak e.
P . 5 0 -3 9
Insulin Doses
I f a t a ll po ss ib le , J . R . s ho u ld us e i ns u li n l is p ro o r i ns u li n a sp a r t t o co ve r m e al s a nd s n ac ks ,
s i nc e t he s e in s ul in s p r o vi d e m a xi m um fl e xi b i li t y fo r u np r ed ic t ab l e me a l d el a ys a n d f oo d
a m ou n ts . J . R . n ee ds to a d ju s t h e r b as al in su li n d o se s wh e n sh e f l ie s ac ro ss se ve r al t im e
zo n e s t o a cc ou n t f o r t ime l os t o r g a in e d. 3 7 W hen t r a vel i ng ea st , th e i ns ul i n d os e s ho u ld b e
d e c re as e d p ro p o rt i on a te ly f o r t he ti me lo st a nd a s h o rt e r d a y. C on ve r se l y, wh e n t r a vel i ng we s t ,
t h e b as a l i ns ul in d os e sho u ld be in c re as e d f o r t he t im e g ai n ed an d a lo n ge r d a y. Th e p ri nc i pl e
i s to pr o vi de th e s am e am o un t o f ba sa l i ns ul i n pe r h ou r . F o r e x a m p l e, if J . R . i s u si ng 10 un i ts
o f N P H an d i s t r a vel i ng fr o m Ne w Yo r k t o Lo n do n ( a 5 -h ou r di f fe r e nc e ), he r d os e wo u l d b e
r e d uc ed t o 8 u n it s . Th i s is be ca u se s h e is r ec ei vin g ab o ut 0. 4 U /h r an d s he wi l l be lo si ng 5
h o u rs as s he c ro ss es the t im e zon es ( 0. 4 × 5 = 2 U ) . W hen sh e a r r i ves in L on d on an d c ha n ge s
h e r wa t ch , s h e ma y r e sum e h e r N P H 1 0 u ni t s a t th e us ua l t im e o f ad mi ni st r a t io n . W hen
d r a wi n g u p h e r i ns u li n do s e wh i l e o n a n a i rp l an e, J . R . sh o ul d i nj ec t on l y h a l f as mu ch ai r i n to
t h e via l ; b ec au se t he c a b i n p r es su r e i s lo we r t h an g r ou nd p re ss u re , l es s p r e ss u re i s n e ed ed
i n si de t he vi al to ba l an ce t he in su l in s h e wi t h d r aws .
Jet Lag
B e c au se je t l a g ma y b e in d is t in gu is h ab l e f r om s ym p to ms of h ypo g l yc e mi a o r h ype r gl yc em i a,
J . R . s ho u ld te s t h e r bl o od g lu co se co nc en t r at i on s m o re f re q ue n tl y t o b e tt er a ss es s h e r
s ym p to ms .
Perioperative Management
A. G . , a 2 7 - ye a r - o l d , 6 0 -k g w o ma n w i th a 1 5 - ye a r h i s to r y o f t yp e 1 d i ab e t e s, w a s a dm i t te d
t o t h e h os p i t al f o r a n ab d o m in a l h ys t e r e c t o m y. B e f o r e a dm i ss i o n, she h as b ee n w el l
c o n t r o ll e d o n 2 4 u n i ts in s u l in g la r g i ne at b ed t im e an d p re m ea l d o se s o f i n su l in a sp a r t .
A. G . w il l r ec e i ve h e r usu a l do s es o f i ns u l in p lus s up p l em e nt a l d o se s o f i n su l in a cc o r di n g
t o a s l i di n g s c al e . H ow s h o u ld A. G . ' s d ia b et e s b e ma n ag e d p e r i op e r a tive l y?
P e r i op e ra t i ve m an a ge men t o f a p a ti e nt wi t h d i ab et e s i s co mp l e x b ec a us e s o m an y va r i ab l es
c a n i nf l ue nc e i ns u li n r e qu i r em en t s. Ac c or d in gl y, c om mo n p r ac t ic e h as bee n to ai m f o r b lo o d
g l uc os e c on ce n t ra t io ns in t he r an g e o f 1 50 t o 2 00 mg / dL . H o we ve r , a st ud y o f I C U p a ti en t s
wi t h h yp e r gl yc em ia , i n wh i ch li be r a l g lu co se c o ntr o l (b l oo d g lu c os e co nc en t r a ti o ns o f 1 8 0 t o
2 0 0 m g/ d L ) wa s co mp a red wi t h t ig h t co n t ro l (b lo od g lu co se co nc en t r at i on s o f 80 to 11 0 m g/ d L ),
h a s ca l le d t h is p r ac t ic e in t o q u es ti o n. S u r vi val r at e as we l l a s i nc id en c e of s ys te mi c i nf ec t io n
wa s s i gn if ic a n tl y b et t e r in t he ti g h tl y co n t ro ll e d gr o u p . 1 09 A no t he r p ro sp ec t i ve r a nd om i ze d t r ia l
( D I G A MI t r i a l ) c om p a re d i n te ns i ve i ns u li n t h e ra py ( i n su li n gl uc os e i n fu si on f o r a t l ea s t 2 4
h o u rs fo l lo we d b y S C i nsu l in f ou r ti me s d ai l y fo r a t le as t 3 mo n th s ) i n p at ie n ts wi t h di ab e te s
a f t e r ac u te MI wi t h s t an da r d th e ra p y. In t en si ve ins u li n t h e ra p y im pr o ve d lo n g - te rm su r vi va l a t
o n e yea r an d c on t in u ed fo r 3 .5 ye a rs , wi t h a n a bso l u te ri sk r ed uc t io n i n mo r t al i t y of 11 % . 1 1 0
Th u s , s t ud i es s ug g es t t ha t h ype r g l yc em i a is a r isk f ac to r fo r ad ve r se ou t co m es i n a cu t el y i ll
p a t ie n ts , a n d t re a tm e nt to ma i nt a in go o d gl yc em ic co n t ro l s ho ul d b e u se d. 1 1 1 Ma n y
a p p ro ac h es to th e m an ag e me n t o f s uc h p at i en ts h a ve be e n su g ge st e d i n t h e l i te r a tu r e . 1 12 , 11 3
Mo s t p r o t oc ol s i nc lu de th e us e o f i n tr a ve no us r eg u la r in su l in an d 5 % t o 10 % gl uc os e . Th e s e
i n cl ud e :

Th e a dm i ni st r a ti o n o f o ne - t hi r d to on e -h a lf th e tot a l d a il y d os e as in t e rm ed i a te - ac t in g
i n su li n b e fo r e s u rg e r y and p os to p e ra t i vel y a lo ng wi t h a 5% de xt r o s e s o lu ti o n a t a r at e
o f 10 0 to 20 0 m L/ h ou r . Th i s is ac co mp a ni ed b y su p pl e me n ta l r a pi d o r s h or t - a ct i ng
i n su li n d os e d s ub cu t an eo u sl y ac c or d in g t o b l oo d g l uc os e c on ce n tr a ti o ns .

A d m in is t ra t io n o f a co mbi n ed in su l in an d g l uc os e i n f us io n a t a fi xe d r a t e . A p o pu la r
s o lu t io n i s 2 0 u ni ts o f r eg u la r in su l in an d 2 0 m E q K C l in ea ch li t e r o f 5 % d e xt r o s e i n
wa t e r a dm i ni st e r ed at a ra t e o f 10 0 m L/ h ou r . Th e a d va n ta g e o f t hi s a p pr o ac h i s t h at if
t h e g l uc os e i nf us i on is ac ci d en t al l y di sc on n ec te d o r ob st r uc t ed , th e i ns u lin i nf u s i on wi l l
a l so be s t op p ed . Th us , th e ri sk of h yp og l yce mi a is es se n ti al l y el im i na t ed . Th e
d i sa d va nt a ge to t hi s a ppr o a ch is t h at i t e li mi na t es t he ab il i t y to c h an g e t he d el i ve r y
r a t e o f o n e a ge n t wi t ho ut c ha ng i ng th e d e li ve r y ra t e o f th e o t he r .

A d m in is t ra t io n o f a se p ar a t e c on t in u ou s i ns ul in in f us i on ( us ua ll y 1 00 un i ts o f r eg u la r
i n su li n i n 1 0 0 mL no r ma l s al i ne ) an d g lu co se ( usu a ll y d e xt r o s e 5 % i n wa t e r a t 1 00 to
1 2 5 m L/ h ou r ) de li ve r e d b y d e di ca t ed pu mp s t o al l o w f o r i n de pe n de n t a dju s tm en t s o f
e a ch . Th e i n fu s i on r at e of e ac h s ol u ti on is de t e rmi n ed b y c a pi ll a r y bl o od gl u co se le ve ls
e ve r y 1 t o 2 h o ur s .
Th e l as t of th es e o p ti o ns s ee ms m os t ap p ro p ri a t e. I t e l im in a te s t he un ce r ta i n p ha r ma co ki n et ic s
o f su bc u ta n eo us l y ad mi ni s te r e d i nt e rm ed i at e - ac tin g in su li n a n d, u nl ik e o pt i o n 2 , a ck no wl e d ge s
t h a t g lu co se u ti li za t io n an d in su li n re sp o ns e m a y b e al t e re d i n s uc h p at i ent s . I ns u li n i n fu si o n
m us t be s t a rt e d a t l ea s t 2 t o 3 ho u rs be f or e th e su r g e r y to ti t r at e to th e de s i re d l e vel o f
g l uc os e c on t r ol . O th e r f lu i d a nd el e ct r ol yt e re q uir e m en ts a re ad mi ni s te r ed t h ro u gh a se p a ra t e
l i ne . To s u cc ess f ul l y mon i t or a nd re g ul a te th e i ns u li n i n fu si on r eg im e n, ac cu r a te be ds i de
m e as u re me n t o f b lo o d g lu c os e l e vel s i s ma n da t ory. A r e p re se n ta t i ve p r ot oc o l f o r a n i ns ul i n g l uc os e i n fu si o n d ur i n g th e pe r io p e ra t i ve p er i od is as fo l lo ws :
Blood Glucose (mg/dL)
Insulin Infusion
mL/hr
U/hr
D5W infusion (mL/hr)
<70*
0.5
0.5
150
71–100
1.0
1.0
125
101–150
1.5
1.5
100
151–200
2.0
2.0
100
201–250
3.0
3.0
100
251–300
4.0
4.0
75
>300
6.0
6.0
50
*Give 10 mL D5W IV and repeat blood glucose measurement 15 minutes later
Th u s , A . G . 's us ua l d os e o f in su l in s h ou ld b e di sco n t in ue d , a n d sh e s ho u ld b e i ni t ia t ed on an
i n su li n i n fu si o n t ha t is ad j us t ed ac co r di n g t o a n a l go r i th m si mi l a r t o t he af o r em e nt i on ed
s u gg es t io n . Th r o u gh o ut th e pe r io p e ra t i ve p er i od , s h e sh o ul d re ce i ve a m i ni m um o f 10 0 g
g l uc os e d a il y t o p r e ven t s t a r va ti on ke t os is . I f b e ds i de m e as u re me n ts o f glu c os e a r e
i m po ss ib l e, an y o f t h e op t i on s su g ge s te d m a y b e u se d .
Alternative Routes of Administration
W . C . is a 2 2 - ye a r - o l d ma l e c o l le g e s t ud e n t w i th t yp e 1 d i ab e t es , w ho i s c u r re n t l y i n j e c t i n g
m u l t ip l e d o se s o f i ns u lin l i sp r o t h ro u g ho u t th e d a y a n d i ns u l in g la r g in e a t b e dt i me ;
h ow e ve r , h e f i nd s th e tr a d i t i on a l i n su l i n i n je c ti o n p r oc es s us i ng vi a l s a n d
P . 5 0 -4 0
s yr i n g e s t i m e - c on s um in g a nd cu m be r s om e . He w o u l d l i ke t o f i nd a n e a s ie r , mo r e
c o n ve n ie n t , a n d m o r e di s c r ee t w a y t o i n j e c t his i n su l in w h i le a t s ch oo l . Wh a t i n s ul i n
d e l i ve r y d e vi c e s a re a va i l a bl e fo r W . C. ? Wh a t a l t e r na t i ve r o u te s o f ins u l i n d el i ve r y m a y
b e a va i la b le f o r W . C . i n t h e fu t u r e?
Pen Devices and Prefilled Syringes
P e n de vi ce s a nd p re f il led s yr in g es e l im in a te th e n e e d t o ca r r y s yr in g es an d in su li n via ls
s e pa r a te l y. I n su li n p e ns a r e a vai la b le as p r e fi ll e d p e ns , wh ic h a r e d is po s ab l e , o r re us ab l e
p e ns . P re f il le d p e ns c o nta i n a bu il t - in , s in g le - us e i n su li n c a r tr i dg e . E ac h ca r t r id g e h ol ds 15 0 t o
3 0 0 u ni t s ( 1 .5 to 3 .0 m L ) o f i n su li n l is p ro , re g ul a r, i ns ul i n as p a rt , N P H , 7 0/ 3 0 , Hu ma lo g Mi x
7 5 / 25 , o r N o vol o g Mi x 7 0 / 3 0. P r ef i ll ed pe ns a re h e lp f ul f or p at ie n ts wh o h a ve di f fi cu l t y
h a n dl in g t h e c ar t r id g es in r e us ab le pe n s o r f o r pa t i en ts wi t h bu s y s ch e dul e s wh o p r ef e r n o t t o
h a ve to ch a ng e c ar t r id g es . H o we ve r , p r e fi ll e d p ens a re sl ig h tl y mo r e e xp e n s i ve t ha n a du r a bl e ,
r e u sa bl e p e n, a f ac t o r t ha t mu st be t ak en in t o acc o un t fo r W .C . W it h t he re u sa b le pe n , t he
p a t ie n t i ns e rt s a n i ns u l i n c a rt r i dg e i n to th e p e n 's d e li ve r y c ha mb e r . Th i s m a y al l o w g r ea t e r
f l e xi b i li t y f o r so me pa t ien t s , su ch as th e a b il i t y to ch a ng e t h e t yp e o f i nsu l in in j ec te d wi t ho u t
n e e di ng t o p ur ch a se an ot h e r p e n i f t he in su l in p re sc r i pt i on c h an g es . A l tho u g h t he pe ns a re
r e u sa bl e , p a ti en t s a r e ad vi s ed to us e a ne w d i spo s ab l e n ee dl e fo r e ac h in j ec t io n . Th e se
d e vi ce s d el i ve r d os es up t o 30 un i ts ( B - D ) o r 7 0 u n i ts ( No vo P e n 3 ) o f i nsu l in in 1 -u n it
i n c re me n ts ; t h e B D P en Mi n i a n d No vo P e n Ju n io r d e li ve r do se s u p t o 1 5 an d 35 un i ts
r e s pe ct i ve l y i n ½ - un i t i nc r em e nt s . 6 2
Th e p e ns a r e p a r ti cu la r l y u se f ul f or pa t ie n ts wi t h ( 1 ) r eg im e ns c on si s ti ng o f mu l ti pl e d a il y
d o se s o f ra pi d - o r s h o rt -a c ti n g i ns ul in be f o re mea l s a nd s n ac ks (s uc h a s W .C. ) , (2 ) a f ea r of
n e e dl es , (3 ) i mp a i re d h an d de xt e r i t y, ( 4 ) h ec ti c wo r k /l i fe st yl e o r ( 5 ) f o r t r ai n in g a l te r n at e
i n su li n a dm i ni st e rs (s c hoo l nu r se , s ib li n gs ) .
Insulin Pumps
I n su l in pu mp s we r e d is cu ss e d i n Q u es t io n 3 an d h a ve be e n r e vi e we d e ls ewh e r e . 6 4
Inhaled Insulin
P u l mo na r y a dm in is t r at i on o f i ns ul i n is un d e r a gg re ss i ve i n ve st i ga ti o n a s a s ub s ti t ut e f o r ra p id o r sh o r t -a ct i ng i n su li ns be f o r e me a ls (i . e. , b a sa l in s ul in mu st st i ll b e gi ve n b y i nj ec t io n ) . O n s e t
o f ac t io n i s mo r e ra pi d th a n s ub cu t an e ou s r e gu la r in s ul in ( pe ak 5 t o 6 0 m i nu t es ) .
B i o a vai l ab il i t y of in h al ed i ns u li n i s l o w co mp a r ed wi t h r e l at i ve t o s u bc ut a ne o us in su li n (8 % to
2 5 % d e pe nd i ng on th e s tu d y) , bu t a d va nc es in del i ve r y s yst em s h a ve e nha n ce d t h e
r e p r od uc i bi li t y o f d os e de l i ve r y. 11 4 Th e C oc h r ane G r o up co mp le t e d a m et a - a na l ysi s t o
“ c om p a re th e e f fi ca c y, ad ve r s e e f fe ct s a nd pa t ien t ac ce p ta bi l it y o f i n ha led ve r su s i nj ec t ed
i n su li n . ” 1 1 5 S i x r a n do mize d co n t ro l le d t r ia ls in wh i ch in ha l ed in su l in wa s u s ed to t re a t t yp e 1
o r t yp e 2 d i ab e te s m et the i r c r i te r ia fo r in cl us i on . I n h al ed in s ul in p ro vi de d c om p a ra b l e g l yc emi c
c o nt r o l, an d t h e re wa s no d if f e re nc e i n h yp o gl yce m ic e ve n ts in fi ve o f t he si x s t u d ie s. P at i en t
s a ti s fa ct i on an d q u al it y o f li f e me a su r es we r e h ig h e r f o r i nh a le d i ns u li n. L o n g - t e rm
c o ns eq u en ce s o f t h is d e li ve r y r o u te a re ye t u nk nown a n d qu es t io ns ha ve be e n ra is ed wi t h
r e g a rd to i ts c os t e f fe c tive n e ss an d c li ni ca l o u tco m es . 1 1 6
Adverse Effects of Insulin
Hypoglycemia
G . O . , a 42 - ye a r - o l d , s l ig h t l y o ve r w e i g h t ( 5 ′1 1 ″, 1 80 l b ) m an , ha s h a d a h i st o r y o f t yp e 1
d i a be t e s m el l i t us f o r 17 ye a r s . G . O . ' s m e di c al c a r e w as s p o r ad i c u n t il 1 ye a r a g o w he n h e
r e f e r r e d h i ms e l f t o a d ia b e t es cl i n ic be c au s e he w a s b e g in n in g t o d e ve l o p p a in a nd
n u m b ne ss i n h i s f ee t . At t h a t t i m e, he w a s p oo r l y c o n t r o l l e d o n a si ng l e da i l y d o s e o f 45
u n i t s Hu m ul i n 7 0 /3 0 . H e h ad n o t b ee n te s t in g h i s bl o o d g l uc o se co n ce n t r a t io n s , a nd h is
A 1 C w a s 13 %.
O n p h ys i c a l e x a mi n a ti on , G . O . w a s f o un d t o h ave a n e le va t e d B P ( 16 0 /9 4 mm H g ),
b a c kg r o u nd r e t in o pa t hy, a n d d e c r ea s ed pe d a l p u l se s b i l at e r a ll y. H e h a d de c r ea se d
s e n sa t i on t o vi b ra t i on a n d m o n o fi l am e n t t es t in g i n b o t h f ee t . G . O . a ls o co m p la i ne d of
i m p o te n ce an d “ s ho o t in g p ai n s” in b ot h le g s. A s p o t c o ll e c ti o n f o r mic r o a l bu m in u r i a w a s
4 5 0 µ g o f a l b um i n/ g c r ea t i n i ne ( no r m al , 3 0 –2 9 9 m g / g c r ea t i ni n e ).
G . O . w as t r ea t e d w i t h m u l t ip l e d a i l y d o s e s o f i n s u li n . O ve r t he la s t se ve r a l mo n t hs , he
h a s b e en t r e at e d w it h th e f o ll ow i ng r e gi m en : 1 4 t o 1 8 un i t s i ns u l in asp a r t / 22 un i t s L en t e
b e f o r e b r e ak f as t ; 1 4 t o 1 8 un i t s i n su l i n a sp a r t b e f o r e l u nc h ; 1 6 to 18 u n i t s i n su l i n a sp a r t
b e f o r e d i nn e r ; a n d 2 4 un i t s Le n te a t b e dt i me . B l o o d gl u co s e c o nc en tr a t i o ns h a ve b e en as
f o l l ow s :
Time
Glucose Concentration (mg/dL)
7 AM
60–320
Noon
140–280
5 PM
40–300
O ve r t h e p as t ye a r , G . O . ' s A 1 C h as d ec r e as e d to 7 . 1 %. C u r r e n t l y, h e h a s ap p r o xi m at e l y
f i ve h yp o g l yc e m i c e p iso d e s p e r w ee k , p r i ma r i ly i n t h e l a t e a f te r n o on a n d e ve n i n gs . Th e se
a r e ch a r ac t e r iz e d b y i n t e n s e h un g e r , sw e a ti n g, p a lp i t a ti o ns , an d (a c co r d i n g t o hi s w i fe ) a
s h o r t te m pe r . H e h as f ou n d t ha t he ca n a vo i d no c t u r na l h yp o g l yc e m i a ( n i g h t sw e a ts ,
n i g h tm a r es , an d he a dac h e s ) b y e a t i n g a la r g e b e d t im e s n ac k . O ve r t he p as t 3 m on t h s , h e
h a s g a i ne d 1 5 lb . Ar e G . O . ' s si g ns a nd s ym p t o m s co n si s t en t w i t h m i ld , m od e r a te , o r
s e ve r e h yp o g l yc e m i a ? W h a t a r e th e c a us e s?
[ S I un i ts : b l oo d g lu c os e 7 A M, 5 . 5 to 8 .3 m mo l /L ; 1 2 P M, 1 5 .5 m mo l /L ; 5 P M, 2 . 2 t o 1 5 .5
m mo l /L ; A 1 C , 0 .7 2 ]
G . O . ' s ca s e il l us t ra t es on e of t he m a jo r h a za r ds o f in t en si ve in su l in th e r ap y: h yp o gl yc em ia .
H yp o g l yce mi a i s a fa c t of l if e fo r p a ti e nt s wi t h t yp e 1 d ia b et es , vi rt u al l y al l of wh o m e xp e r i e nc e
a h yp og l yce mi c e pi so d e a t on e ti me or an o th e r . An es t im a te d 4 % o f d e at hs r el a te d t o t ype 1
d i ab e te s a r e c au se d b y h yp o g l yc em i a. 2 1 , 1 17 , 11 8
H y p og ly ce mi a i s a bl oo d g l uc os e c on ce n tr a ti o n of < 60 mg / dL ( <2 . 7 mm ol /L ) , an d i ts oc cu r r en ce
i s p o te n t i a ll y f at a l i f n o t p r o mp t l y re co g ni ze d a nd t r e at e d. H o we ve r , th e exa c t l e ve l a t wh ic h a
p a t ie n t e xp e r i en ce s s ymp t om s i s d if f ic ul t to de f ine . C li n ic al h ypo g l yc em i a i s a ss oc ia t e d wi t h
t yp i ca l a u to n om ic (n e u rog e ni c ) a nd ne u r og l yco p en i c s ymp t oms r el i e ved by t h e ad mi ni s tr a ti o n
o f a q ui ck l y - ab so r b ed c ar b o h yd ra t e .
Pathophysiology
N o r m al b ra in fu n ct i on dep e n ds o n g l uc os e, t he exc l u s i ve fu el f or ce r eb r a l m e ta bo l ism . B ec au se
t h e b r a in i s u n ab le t o s yn t h es i ze o r s t or e g l uc ose , it mu st be p ro vi d ed wi t h a c on st a nt
P . 5 0 -4 1
e xo g e n o us qu a nt i t y via th e b ra in ' s b l oo d s up p l y. A s bl o od gl uc os e c on ce nt r a t io ns fa l l, a s er i es
o f ph ys io l og ic r es po ns es o cc u r t o re st o r e gl u co se l e ve ls . Th es e r es p on se s c r ea t e s ymp t om s
wa r n i n g a pa t ie n t t o ta ke c o r re ct i ve a c ti on b y c o ns um i ng c a r bo h yd ra t es . If t h es e c ou n te r r e g ul a to r y r es p on se s f ai l t o al e rt t he pa t ie n t a nd b l oo d g l uc os e c on ce n t rat i o ns fa ll be l o w a
c r i ti ca l l e vel , c o gn i ti ve fu n ct i on be co me s i mp ai r ed a nd c o nf u si on an d c oma ma y e ns u e.
I n pa t ie n ts wi t h ou t d i ab et e s , t he pe r ip h e ra l r e sp on s es to h ypo g l yc em i a a re so e ff ic i en t t h at
c l in ic al l y im po r t an t h yp og l yc em ia p ro ba b l y n e ve r o cc u rs . As g l uc os e l e vels f al l b et we e n 50 a nd
6 0 m g /d L (2 . 7 t o 3 . 3 mmo l / L) , a se r i es o f ne u ro en d oc r in e e ve n ts oc cu r , ra i si ng t he pl as ma
g l uc os e c on ce n t ra t io n b a ck t o wa r d n o rm al b y in cr e a si ng he p at ic gl uc o se o u t pu t . Th e ma j or
h o r mo ne r es po ns i bl e f o r p r o du ci n g ac u t e r ec o ve ry f r o m i ns ul i n -i nd uc e d hyp o g l yce mi a i s
g l uc a go n ; h o we ve r , e p ine p h ri n e a lo ne al s o ca n pr o d uc e n ea r - n or ma l re cove r y. R i s in g l e vel s o f
a d r en e r gi c a nd c h ol in e r gi c h o rm o ne s g en e ra t e wa r n in g s ym pt om s o f h yp og l yc em ia . W hen
h yp o g l yc em i a is p ro lo n ge d , g r o wt h ho r mo n e a nd c o r ti so n e p la y a g r e at e r r o l e i n p r od uc i ng
r e c o ve r y.
P a t i en ts wi t h t ype 1 d ia be t es wh o ma i nt a in i n su lin d ep o ts th r ou g ho u t t he d a y a r e p r e d is po se d
t o se ve r e h yp og l yc em ic re a ct i on s b ec au se de f ic ien c ie s i n t he no r ma l f e edb a ck s ys t em o cc u r
o ve r t im e. G l uc ag o n se cr e t io n be co me s d ef ic i en t wi t h i n th e f i rs t 2 to 5 yea r s a f te r di a gn os is ,
a n d b y ≥ 1 0 yea r s, ep i nep h r in e s ec r e ti on ma y b ec om e i mp a i re d . T h e la t ter d e fe ct le a ds to
a s ym pt om a ti c h yp og l ycem i a o r h yp o gl yc em ic u n awa r e n e ss (s e e Q u es t io n 3 9 ) .
C e r t a in c i rc um st a nc es p re d is p os e p at i en ts wi t h t yp e 1 d ia b et es to se ve r e h yp o g l yc em i a. Th e se
i n cl ud e (1 ) a d ef ec t i ve co u n te r - r eg ul a to r y h o rm on a l r e sp on se t o h yp og l yce m ia (s e e Q u es t io n
3 9 ) , (2 ) m e di ca ti o ns s uch as β - bl oc ke r s t h at di min i sh ea r l y wa r n in g s ig ns o f im pe n di ng
h yp o g l yc em i a, ( 3 ) i nt e nsi ve i ns ul in t he r ap y t h at ca n al t e r se c re t io n o f c oun t e r - re g ul a to r y
h o r mo ne s , ( 4 ) sk i pp e d me a ls o r i na de q ua t e ca r b oh yd r a t e i nt ak e re la t i ve t o t h e i ns ul i n d os e, ( 5)
p h ys ic al ac ti vi t y, an d (6 ) e xc e s si ve al co h ol in t a ke ( Ta b le 5 0 - 2 5 ).
Symptoms
Th e s ig ns an d s ym pt om s a ss oc ia t e d wi t h h ypo g l yc em i a va r y i n i nt e ns it y ac co r d in g t o t h e
p r e se nc e o f c og n it i ve d ef i ci t s a nd th e p a ti e nt ' s ab i li t y t o s el f -t r e at t he re ac t io n . Th e y va r y
s u bs ta n ti a ll y f r om o n e pa t i en t t o an o th e r. S ym pto ms a re co n ven t io n al l y di vi d ed in t o t wo
c a te g o ri es : n e u ro ge n ic (o r a ut o no mi c) a nd ne u rog l yc op e ni c. 1 17
A u t o no mi c sy mp t o ms in cl u de s we a ti n g, in t en se hu n g er , pa lp i ta t io ns , t re mo r , ti n gl in g , a nd
a n xi e t y. E p in e ph r in e i s th o u gh t t o m ed i at e m an y o f t he ne u ro g en ic r es po ns es t o h yp og l yce mi a .
N e u r o gl yc op en ic sy mp toms r e su lt i ng f ro m n eu r o na l fu e l d ep r i va ti on ( gl uc os e ) i nc l ud e d i ff ic u lt y
c o nc en t r at i ng ; l e th a r g y; c o nf us i on ; a g it a ti o n; we a k ne ss ; a n d p oss i bl y, slu r r e d sp e ec h ,
d i zzi n es s, a nd fa in t in g . P r o f ou n d b eh a vi o ra l c han g es , s ei zu r es , an d c oma a r e mo r e s e ve re
m a ni f es ta t io ns o f n eu r ogl yc o pe n ia . P ro lo n ge d , seve r e n eu r og l yco p en i a u lti m at e l y re su l ts i n
d e a th . S ymp t oms o f mi ld, m od e ra t e, se ve r e , a nd n o ct u r na l h yp o gl yc em ia a r e as f o ll o ws :

Mi l d h y po gl yc e mi a: S ymp t om s i nc lu d e t r em o r, pal p i ta t io ns , s we a t in g , a nd i n te ns e
h u n ge r . Di mi ni sh e d c er eb r a l f u nc ti o n is no t p r es en t an d p a ti e nt s a r e c ap ab l e o f s el f t r e a ti n g mi ld r ea c ti on s .
Table 50-25 Hypoglycemia
Definition
Blood glucose concentration <60 mg/dL; patient may or may not be symptomatic.
Blood glucose <40 mg/dL; patient generally symptomatic. Blood glucose <20
mg/dL can be associated with seizures and coma.
Signs and Symptoms
Blurred vision, sweaty palms, generalized sweating, tremulousness, hunger,
confusion, anxiety, circumoral tingling and numbness. Patients vary with regard to
their symptoms. Behavior can be confused with inebriation. Patients become
combative and use poor judgment.
Nocturnal hypoglycemia: nightmares, restless sleep, profuse sweating, morning
headache, morning “hangover.” In one study, 80% of patients with nocturnal
hypoglycemia had no symptoms.
Clinical Considerations
Irregular eating patterns
↑ Physical exercise
Gastroparesis = (delayed gastric emptying time)
Defective counter-regulatory responses
Excessive dose of sulfonylurea
Alcohol ingestion
Drugs
Treatment
10–20 g rapidly absorbed carbohydrate. Repeat in 15–20 min if glucose
concentration remains <60 mg/dL or if patient is symptomatic. Follow with complex
carbohydrate/protein snack if meal time is not imminent.
The following are examples of food sources that provide 15 g of carbohydrate:
Orange, grapefruit or apple juice; regular, nondiet soda
½ cup
Fat-free milk
1 cup
Grape juice, cranberry juice cocktail
1/3 cup
Sugar
1 T or 3 cubes
Lifesavers
5–6 pieces
Glucose tablets
3–4 tablets
If patient is unconscious the following measures should be initiated:
Glucagon 1 mg SC, IM, or IV (mean response time, 6.5 min)
Glucose 25 g IV (dextrose 50%, 50 mL) (mean response time, 4 min)
IM, intramuscular; IV, intravenous; SC, subcutaneous.

Mo d e r a t e hy po gl yc e mi a: Mo d e r a t e h ypo gl yc em ic re a ct i on s i nc lu d e n eu r og lyc o p en ic as
we l l a s a ut o no mi c s ymp to ms : he ad a ch e , mo o d cha n g es , i r ri t ab i li t y, d e cr ea s ed
a t t en t io n , a nd d ro ws i n ess . P at ie n ts m a y r eq u i re a ss is t an c e i n t r ea t in g t he ms e l ves
b e ca us e o f th e p r es e nc e o f i m pa i re d j u d g me n t o r we a k n es s. S ym pt om s a re mo r e
s e ve r e, us ua l l y l as t lo nge r , an d o f te n re q ui r e a se c on d d os e o f a si mp l e ca r b oh yd r a te .

S e v e re hy po gl yc e mi a: Sym p t om s o f s e ve re h ypog l yc em ia in cl u de un r es po n si ve n ess ,
u n co ns ci o us ne ss , o r c o nvu l s io ns . Th es e re ac t io ns r eq u ir e a ss is t an ce f rom an o th e r
i n di vi d ua l f o r a p pr o p ri a te t r ea tm e nt . A pp r o xi m a te l y 1 0% of pa t ie n ts t re a te d wi t h i ns u li n
d e ve l op at le as t o n e s e ve r e , d is a bl in g e p is od e o f h yp o gl yc em ia pe r ye a r th a t re q ui r es
e m e rg en c y t re a tm en t wi th p a re n te r al gl uc a go n o r I V g l uc o se . 11 7
P . 5 0 -4 2

N o c t ur n al hy po g lyc e mi a: Ti n g li n g o f t h e l ip s a nd t o n gu e a r e c omm o n co mp l ai n ts of
p a t ie n ts wh o de ve lo p n oc t u rn a l h yp og l yce mi a . Th e se pa t ie n ts a ls o m a y co m pl ai n o f
h e a da ch e a nd di f f ic ul t y a r i si ng in th e m o rn i ng , n ig h tm a r es , o r n oc t u rn a l
d i ap h o re si s. 1 17 Fa mi l y m em b e rs s ho u ld be c o nsc i ou s o f a n y un us u al s o un d s o r a c ti vi t y
wh i l e t he pa t ie n t is sl ee pi n g .
G . O . h as mi ld t o mo d e rat e h ypo g l yce mi c r ea c ti ons , wh i ch he is a b le to se lf - t r e at . Th es e a r e
l i ke l y du e t o o ve r i ns ul in iza t i o n.
Overinsulinization
E va l u a t e G . O .' s o ve r al l c o n t r o l. W ha t s i g ns and s ym p t o m s i n G . O . a r e c o ns i s te n t w i th
o ve r i n s u li n iz a t io n ? How sh o u ld he b e m an a ged ?
Th e f o ll o wi n g i s a l is t o f s i gn s a nd s ym p to ms of ove r i n su li n i zat i on in G . O . :

A t o ta l d a il y i ns ul in do s e o f 1. 0 U /k g. Th is do s e is un us u al l y hi g h f o r a p at i e nt wi t h t ype
1 d ia be t es wh o sh ou l d no t be r es is ta n t t o th e a cti o n o f i ns u li n .

W eigh t g a in o ve r t he pa st s e ve ra l m on t hs . Th i s i s s ec on d a r y to th e a n ab oli c e f f ec ts of
i n su li n a s we ll as G . O . ' s i n c re as ed ca r bo h yd r at e in t ak e to m a tc h h is hi gh in s ul in do s es
o r t r ea tm e nt o f h yp og l yce m ia .

F r e q ue n t h yp og l yce mi c re a ct i on s.

A n a pp a re n tl y “ b r it t le ” s it u a ti o n ( i .e . , b lo o d g lu cos e c on c en t ra t io ns t ha t flu c tu a te wi l d l y
b e t we e n h yp o gl yc em ia an d h ype r gl yc em i a) . In G .O . ' s ca s e, hi g h bl o od gl uc os e
c o nc en t r at i on s ma y r e p re s en t re ac t i ve h yp e rg l yce m ia o r o ve r t re a tm en t o f h yp o gl yc em ic
e p is o de s.

N e a r no r ma l A 1 C le ve ls in d ic a te m e an bl o od gl uco s e co n ce n tr a ti o ns th a t m us t be wi t h in
t h e n o rm a l r an g e e ve n th o u gh th e p a ti e nt ha s r ec o r de d n um e ro us hi g h b lo o d g lu c os e
c o nc en t r at i on s. P a ti en t s t r e a te d wi t h i nt e ns i ve i ns u li n t h e ra p y in th e D C CT e xp e r i e nc ed
h yp o g l yc em ic ep is o de s th r e e t im es m o r e o f te n t ha n pa t ie n ts tr e at e d wi t h s t an d a rd
i n su li n th e ra p y. 21 A 1 C l eve l s we r e a p p ro xi m a t el y 7 . 2 %.
G . O . s ho u ld be m a na g ed b y g r ad u al l y de c re as in g h is in su l in do se s. B ec aus e m os t o f hi s
r e a ct i on s a r e oc cu r r in g in t he la t e a f te r no o n a nd e ve n i ng , t h e mo r n in g d os e o f in t er me d ia t e a c ti n g i ns ul in sh o ul d b e a d ju s te d f i rs t . Ch a ng in g h i s i nt e rm e di a te - ac ti n g in s ul in f r om L e nt e t o
i n su li n g l a rg in e a ls o s hou l d b e c on si d er e d f o r t wo r e as on s: ( 1 ) t he e xc e ss zi nc in th e L e nt e
i n su li n m a y be c o n ve rt i ng so me o f t he sh o rt - ac t ing i ns ul in t o a n i nt e rm e dia t e - ac ti n g f o rm (s ee
Q u e s ti o n 1 4) , an d (2 ) the L en t e ma y b e p e ak in g i n th e l a te af t e rn o on an d e ve n in g . Th e t ot a l
d a il y d os e o f i n te r me d ia te - a ct i ng in su li n s ho u ld be r e du ce d b y 2 0% s u bs tit u t ed wi t h a si n gl e
d o se of lo n g -a ct i ng in su li n gl a rg i ne in th e m o rn ing o r a t b e dt im e .
G . O . a ls o s ho u ld be g in te s ti n g h is g l uc os e c on cen t r a ti o ns a t 2 o r 3 A M, an d he s h ou l d b e
t a u gh t to t re a t h is h yp o gl yc em ic ep is o de s a pp r o pr i a te l y ( se e Qu e st io n 38 ). I f h e i s c ap a bl e, an
a l go r i th m f o r a dj us t in g h is p re p ra n di a l as p a rt in sul i n d os es s h ou l d b e p ro vid e d t o m in im i ze
h yp o g l yc em ic an d h yp e rg l yc em ic re ac t io ns ba s ed o n t he “ 18 0 0 R u le ” or s e ns it i vi t y fa c to r (s ee
Q u e s ti o n 1 8 ) . Th e e q ua t io n is a s f o ll o ws :
1 8 0 0/ C u r re n t To ta l Da i l y I n su li n Do s e = Se ns i ti vit y F a ct o r
Th e s en si t i vi t y f a ct o r f o r G . O . ( us i ng hi s n e w d ose o f L an t us pl us as pa r t do s es p r em e al ) wo u ld
be:
1 8 0 0/ 8 4 = 2 1
Th u s , fo r e ve r y u n it G . O . i n je ct s , h is b l oo d s ug a r wi l l d r op ap p r o xi m at e l y 21 mg / dL . To
f a ci l it a te ea se in un d e rs ta n di n g h is s li d in g s ca le , t h is nu mb e r c an be r ou nd e d d o wn t o 2 0
m g /d L .
A n e xa m p le of an al g o ri th m th a t ma y b e a pp r o pr ia t e fo r G . O . f o ll o ws :
Glucose Concentrations (mg/dL)Change Dose of insulin aspart by:
<60
–2 units
<80
–1 unit
80–100
No change
101–120
+1 unit
121–140
+2 units
141–160
+3 units
161–180
+4 units
181–200
+ 5 units
201–220
+ 6 units
221–240
+ 7 units
G . O . s ho u ld be in st r uc t ed t o t ak e i ns u li n a sp a r t im me d ia t el y b ef o r e e ac h m e al an d a dj u st hi s
d o se ac co r di n g t o t he p re vi o us al g or i th m . I t wi ll b e im po r t an t t h at he r eco r d th e a ct u al do se he
a d mi ni s te r s b ef o r e e ac h m e al an d b r in g th e r ec o rd t o c li ni c s o t ha t h is bas ic do se o f i ns ul in
c a n b e mo r e fi ne l y t u n ed.
Treatment of Hypoglycemia
H ow s h o ul d G . O . 's h yp o g l yc e m i c e p i so d es be m a n ag e d?
A s G . O . i l lu st r a te s , ma ny p a t ie n ts wi t h d i ab e te s a r e f ri gh t en e d o f h yp o glyc e mi a a n d h a ve a
t e n de nc y t o o ve r t r ea t t he i r re ac t io ns wi t h , fo r e xa m pl e , l ar g e q ua n ti t ie s of j ui ce o r se ve r a l
c a nd y b a rs . Th is s ho u ld b e di sc ou r ag e d b ec au s e o ve r c o rr ec t io n to ge t he r wi t h g l uc os e
g e n er a te d b y c ou n te r - r eg u la t o r y ho rm o ne s u l ti ma t e l y re su l ts i n h yp e r gl yc em i a.
Th e k e y to su cc ess f ul ma n a ge me n t o f h yp og l ycem i a is r ec og n it i on an d p re ve n t io n . B e c a us e
e a r l y wa r n in g s ym pt om s o f h ypo g l yce mi a var y f r om pe r so n to pe rs o n, i t is i mp o r ta n t t ha t G . O .
s t ud y a n d le a r n t o r ec o gn i ze hi s e a rl ie s t wa r n i ng s ym pt om s a nd t o t r ea t ea r l y. P at i en ts
g e n er a ll y ca n re ca l l p ro dr o m al s ym p to ms f o ll o wi ng r ec o ve r y f ro m a s e v e r e h yp o gl yc em ic
r e a ct i on if th e y ha ve n ot d e ve l op ed h ypo g l yce mi c u n a wa r e ne ss (s ee Q u est i o n 3 9 ). As a
c a ve at , th es e a u th o rs occ as i on a ll y h a ve se e n p ati e n ts wh o “ fe el ” h ypo g l yce m ic a f t er t he i r
b l oo d g l uc os e c on ce n t rat i o ns h a ve b e en no r ma lize d f r om ve r y hi gh le ve ls wi t h in t en si ve in su li n
t h e r ap y. W e en c ou r ag e p a t ie n ts to te s t t he i r b loo d gl uc os e c on ce n t ra t ion s a n y t im e t he y “ f ee l
u n us u al ” to ve ri f y a l o w b l oo d g l uc os e c on ce n t rat i o n b ef o r e t r ea tm e nt . G .O . s ho u ld t re a t h is
s ym p to ms o n l y i f he is t ru l y h yp og l yce mi c .
A s ec on d c om p on en t of p r e ve n ti on is de t er mi n ing i ts c a us e a nd ta ki n g p re ve n t i ve o r c o r re ct i ve
a c ti o n. Th i s e nt a il s as ses sm e nt of hi s d ie t (d i d he sk ip o r d el a y a m ea l o r c ha n ge it s c on t en t ? ),
e xe r c i s e p at t e rn , a n d t ime o f i ns ul i n a dm in is t ra t ion a nd do se ( an d a cc u ra cy o f d os e
a d mi ni s te r ed ) . If h ypo g l yc em ic r ea c ti on s c on si st en t l y oc cu r at a ce r t ai n t im e o f da y, he sh ou l d
d e t e rm in e wh e th e r t h is co r r es p on ds t o t he m a xi m u m e f f ec t o f o n e o f h is i ns u li n d os es an d
r e d uc e t h at in su l in do se b y 1 t o 2 u n it s . A l te r na t ive l y, h e c an ad d a s u pp le m en t al s n ac k t o t ha t
p a r t o f th e d a y.
P . 5 0 -4 3
I f a re ac t io n o cc u rs , G . O. s ho ul d b e i ns t r uc t ed to t r e a t i t a s f ol l o ws (a ls o se e Ta b le 50 - 25 ) .
Mild Hypoglycemia
Mo s t h yp o gl yc em ic r ea cti o ns a re m a na ge d re a di ly wi t h t h e e q ui va le n t o f 1 0 to 20 g o f g l uc os e.
( S e e Ta bl e 5 0 - 25 fo r e xa m p le s o f c a rb oh yd r a te so u r ce s co n ta i ni n g 1 5 g of g lu co se . ) If t he
b l oo d c o nc en t r at io n re ma i ns lo w a f t e r 1 5 mi n u tes , th e p a ti e nt sh ou l d i nge s t a no t he r 10 t o 2 0 g
o f ca r bo h yd r at e . Th i s q uic k -a c ti ng so u rc e o f g l uco s e sh o ul d b e f o ll o we d by a sm a ll c om p le x
c a r bo h yd ra t e o r p r o te i n s n ac k ( e .g . , mi lk , pe an u t b u t te r s an d wi c h ) t o p r o vi d e a c o nt i nu a l
s o u rc e o f g lu co se i f a me a l i s n ot sc he du l ed wi t hi n th e n e xt 1 t o 2 h o u rs . A n e as y r ul e o f
t h um b th a t ca n b e u se d b y p a ti e nt s i s “ 1 5 - 1 5 -1 5 ”: 1 5 g of gl uc os e fo ll o we d b y a s ec on d 1 5 g if
t h e p a ti e nt is s t il l s ymp to m at ic a ft e r 1 5 m in u te s.
G l u c os e t ab l et s a r e a va ila b le an d ha ve th e a d de d b e ne f it o f b ei ng p re me as u r ed to p re ve n t
o ve r t r ea t me n t o f h yp o gl yc em i a. G l uc os e g el s o r sm a ll tu b es o f c ak e fr os t in g a re us ef u l f o r
c h il d re n o r pa t ie n ts wh o b e co me un co o pe r a ti ve an d c om b at i ve wh e n h yp og l yc em ic .
Moderate to Severe Hypoglycemia
G l u c ag on ca n b e i nj ec t ed b y t he S C o r in t r am uscu l a r ( I M) r o u t e i nt o th e de l t oi d o r a n t er i o r
t h i gh r eg io n . The d os e of g lu ca g on r ec omm e nd e d t o t re a t mo d e ra t e o r s e ve r e h ypo gl yc em i a f o r
a ch i ld yo un g er t ha n 5 ye a r s o f a ge is 0. 2 5 t o 0 .5 mg ; fo r c h il d re n 5 to 10 ye a rs o f a ge , 0 . 5 t o
1 mg ; an d f o r p a ti en t s o ld e r th a n 1 0 ye a rs , 1 mg . P a r en t s a nd s p ou se s s ho u ld be t au g ht ho w t o
m i x, d r a w u p , a n d a dm ini s te r gl uc a go n d u ri n g eme r g en c y s i tu a ti o ns . Ki ts wi t h p r e fi ll e d s yr in g es
c o nt a in in g 1 mg gl uc a go n a r e a va il ab l e. P at i en ts wh o a r e g i ve n g lu ca g on s ho u ld be po si t io n ed
s o th a t t he i r f ac e i s t u rne d to wa r d t he f lo o r t o p re ve n t a s pi r at i on in th e eve n t o f vo mi t in g . A s
s o on as th e p a ti e nt a wa ke n s ( 1 0 t o 2 5 mi n u te s) , h e o r sh e s ho u ld be fe d .
Intravenous Glucose
I f gl u ca go n i s u na va i la b le , t he pa t ie n t sh o ul d b e t a ke n to th e h os p it a l 's ED , wh e r e he o r s he
c a n b e t r ea t ed wi t h I V g lu c os e ( a pp r o xi m a te l y 10 t o 25 g a dm in is t er e d a s 2 0 to 50 mL of 50 %
d e xt r o s e o ve r 1 t o 3 m i nu t es ) in p re f er e nc e t o g lu c ag o n. Fo l lo wi n g th e bo l us in je c ti on o f
g l uc os e , I V gl uc os e (5 to 1 0 g / ho u r ) s ho ul d be c on t i nu ed u nt il t he pa t ie n t h a s g ai n ed
c o ns ci ou sn es s a n d is abl e to ea t .
Hypoglycemic Unawareness
M . M. , a 35 - ye a r - o l d , 75 -k g , un e mp l o ye d m a n , ha s ha d t yp e 1 d i a be t e s s i n ce t he a ge o f 3 .
As a c o n se q ue n ce o f t he d i ab e te s , h e h a s d e vel o p e d p r o li f e r a ti ve r e t in o p a th y a n d
p r o g r e ss i ve d ia b et i c n ep h r o p a th y ( c u r r e n t S r Cr , 3 . 0 m g/ d L ) . M .M . h as a n e r r at i c l i f es t yl e .
B e c a us e h e do e s n o t w o r k , he o f te n s t a ys o u t l a t e a t ni g h t a n d s le e ps l a t e i n t o t h e
m o r n i ng . H is i ns u l in is i n j e ct e d w he n e ve r h e aw a ke n s, an d hi s m e al s a r e i r r eg u l a rl y
s p a ce d . E a ch t im e he co m e s t o th e c l i ni c , h e br i n g s w i th h im a c om p le t e lo g o f g lu c os e
c o n ce n t r a ti o ns t ha t r a ng e f r om 80 t o 1 4 0 m g/ dL . H e h a s tw o t o t h r ee s e ve r e h yp o g l yc e m i c
r e a c t io n s a mo n t h t h a t r e q u i r e e me r g e nc y t r e a t m e n t w it h I V g l uc o se . O n s e ve r a l
o c c as i on s , h i s b l oo d glu c o se co n ce n t r a ti o n h as b ee n 20 mg / dL . M . M. 's l as t A 1 C w as 10 %.
H e s a ys t h a t h e a d h e res t o th e fo l l ow in g in s u li n r e gi m en : 1 8 u ni t s N PH / 1 1 un i t s r e g ul a r
i n s u li n be f o r e b r ea k f ast , 1 0 u n i ts r eg u l a r i n su li n b e fo r e l u n ch an d di nn e r , an d 1 4 un i t s
N P H a t b ed t i me .
O n t h i s vi si t , M .M . c o me s w i t h h i s g i r l f ri e n d. He h as a l a r ge g as h o n hi s n os e th a t
o c c u r r ed 3 d a ys a g o w h e n he lo s t c o ns c i ou s ne s s a t ap p r o xi ma t e l y 1 : 3 0 PM w h i le pu s h in g
h i s st a l le d c a r . He w a s u n a b le t o e a t l un c h a t th e us u a l h o u r b ec a us e h e ha d p r ob l em s
w i t h h i s c a r. As s e ss M.M . ' s h yp o g l yc e m i c r e act i o n s a n d b l oo d gl u co se c on t r o l . S h o ul d
i n t e ns i ve i ns u l in t he r ap y b e c o n t i nu e d ? H ow s h o u ld he b e m a n a ge d?
[ S I un i ts : S r C r, 26 5 µm ol/ L ; bl oo d g l uc os e, 4 .4 to 7 . 8 m mo l /L ; A 1 C , 0. 1 0]
M. M. i l l u s t ra t es a pa t ie n t wi t h t yp e 1 di a be t es wh o h as d e fe c ti ve gl uc os e c o un t e r - r e gu la t io n
a n d , as a r e su l t, is u n ab le t o c ou n te r ac t a h ypo g lyc e mi c re ac t io n e f fe c ti vel y. H e al so is a n
e xa m p l e o f a pa t ie n t who sh o ul d n o t b e t r ea t ed wi t h i n te ns i ve i ns u li n t h er a p y ( se e Ta bl e 5 0 1 5 ) . 93
M. M. c l e a r l y is u n ab le t o a d he r e t o a n i n te ns i ve re g im e n. H is l i fe s t yle is er r a t ic , h e e a ts
i r r e gu la r l y, an d h is re p o rt e d b l oo d g lu c os e co nc en t r a ti o ns (8 0 t o 1 4 0 mg /d L ) do no t c o r re sp on d
wi t h h is el e va te d A 1 C va lu e . Th is m a y in d ic at e t ha t M. M. ' s t e ch n iq ue is inc o r re c t o r t h at he
s im p l y fi ll s i n t he lo g wi th f ic ti t io u s n um be rs b ef or e h e co me s t o t h e cl i ni c. I r r eg u la r e n t ri es in
d i f fe r e nt c o lo r ed in ks and b lo od st a in s us u al l y ind i ca t e a ut h en t ic re co r ds .
M. M. h a s d e vel o pe d a d va n ce d , l on g - te r m co mp l ic a ti o ns th a t a r e u nl ik el y t o be r e ve rs ed b y
i n t en si ve in su li n th e ra p y. I n f ac t , p r ol i fe r a ti ve r eti n op a th y m a y ac tu a ll y wo r s en wi t h i n te ns i ve
i n su li n th e ra p y in i ti a ll y. 21 I n t h e D C C T s t ud y, seve r e h yp og l yce mi c r e ac tio n s we r e t h re e t im e s
m o r e co mm on in pa t ie n ts t re a te d wi t h i n te ns i ve in s ul in t he r ap y, a nd no ctu r n al h ypo g l yc e mi a
a cc o un t ed f or 41 % o f the t o ta l h yp og l yce mi c e pis o de s. 2 1 I n p a ti e nt s wi t h d e fe c ti ve c o un t e r r e g ul a ti o n, t he ri sk of seve r e h yp og l yce mi a m a y b e 25 ti me s h ig h e r t ha n in p at i en ts wi t h
a d e qu a te c o un t e r - r e gu lat o r y me c ha ni sm s t r ea t ed wi t h i n te ns i ve i ns ul i n t he r a p y. 11 7 M. M. i s a t
g r e a t r is k f o r d ea t h se c on d a r y to h ypo g l yc e mi a.
A s p re vi o us l y n o te d , t h e p r i ma r y ho r mo n es th a t ar e se c re t ed in r es po ns e to a l o w b l oo d
g l uc os e c on ce n t ra t io n a re g lu ca g on an d e p i n ep h ri n e . I n p a ti en t s wh o h a ve h ad t ype 1 d ia b et e s
f o r >2 t o 5 yea r s, a d e fi ci e nc y i n g lu ca g on s ec r e tio n is a r el a ti ve l y c o ns is te n t fi nd i ng , a n d
t h es e p a ti e nt s m us t r e l y o n ep in e ph r in e to r e ver se l o w b lo o d g lu co se c o nc e nt r a ti o ns .
U n f o r tu n at e l y, a pp r o xi ma t e l y 4 0 % o f p a ti en t s wi t h l on g -s t an di n g t yp e 1 dia b e te s ( 8 t o 15
ye a r s ) h a ve d e fe c ti ve epi n ep h r in e s ec r et i on as we l l , a nd th is m a y b e r el a te d to t he
d e ve l op me n t o f a ut o no mi c n e u ro pa t h y. Pa t ie n ts wh o s e di a be t es i s c on t r ol l ed cl os el y wi t h
i n t en si ve in su li n th e ra p y a ls o h a ve re d uc ed c o unt e r - r eg u la t or y h o rm on e re s po ns es t o
h yp o g l yc em i a. As il l us t rat e d b y M. M. , p a t i en ts wi t h d ef ec t i ve e pi n ep h ri n e s ec r e to r y r es p on se s
a l so lo se th e wa r n in g s ign s a n d s ymp t om s o f h ypo g l yce mi a . Th e se p at ie nt s ar e s ai d to ha ve
“ h yp o gl y c em i a u na wa r e ne ss ” be ca us e th e y ha ve n o a wa r e ne ss o f bl oo d gl u co se c o nc en t r at i on s
< 5 0 m g /d L . I n t he s e in d ivi d u al s , l oss o f co ns ci o us n es s, s e i zu re s, o r i r ra t io n al be h a vio r m a y b e
t h e fi rs t ob je c ti ve s i gn s o f e xc e e di ng l y lo w b l o od g l uc os e c on ce n tr a ti o ns . Th e g l yce mi c
t h r es h ol d f o r s ymp t om s a l so is l o we r e d i n p a ti ent s on in t en si ve in su li n the r a p y wh o se gl uc os e
c o nc en t r at i on s h a ve b een l o we r ed t o n o rm al or ne a r - no r ma l l e vel s . 1 17 Co n se q ue n tl y, th e i r
h yp o g l yc em ic r ea ct i on s m a y go un n o ti ce d a nd un t r e at e d
P . 5 0 -4 4
u n t il th e y lo se co ns ci o usn e ss . M. M. s h o u ld be m an a g ed as f o ll o ws :

B e c au se hi s wa k i ng , s l ee p in g , a n d e at i ng pa t te rn s a r e h i gh l y ir r e gu la r , M. M. s h o u l d b e
t r e a te d wi t h a n i ns ul i n r eg i me n t h at ad d r ess es his li f es t yl e. Fo r e xa m pl e , h e c o ul d b e
i n st r uc t ed to gi ve hi ms e lf i ns ul i n li s pr o o r as pa r t j u st be f o re he ac t ua ll y i nt e n ds to ea t .
A d os e o f i n su li n g l ar g ine co u ld be gi ve n b e fo r e h i s f i rs t m ea l t o s up p l y a b as a l l e vel of
i n su li n b e t we e n m ea ls . Eve n i n g d os es o f N P H s ho u ld be el im i na t ed be cau s e o f t h e
d a n ge r o f s e ve r e h yp og lyc e mi c re ac t io ns .

B e c au se M. M. h a s n o w ar n i ng s ym p to ms fo r h ypog l yc em ia , th e i mp o rt a nce o f r e gu l ar
b l oo d g l uc os e t es t in g s ho u ld be em p ha si ze d . W he n bl oo d gl uc os e t es t in g wa s r e vi e we d
wi t h M. M. , i t wa s d is co ve r e d t h at hi s e ye si gh t wa s s o p o or t ha t h e wa s un a bl e to
d i st i ng ui sh b et we e n th e r i g ht a nd wr o n g s id e o f th e gl uc os e t e st s t r ip . Fur t h e rm o re ,
b e ca us e h e h a d l os t h is d e p th of f ie ld , he wa s u na b le t o a pp l y th e d r o p o f b l oo d o n to
t h e te st st r ip . To ad d re ss t hi s si t ua t io n , M. M. ' s g i r l f ri e nd wa s ta ug h t h o w t o pe r f o rm
b l oo d g l uc os e t es t in g .

M. M. ' s g i rl f r ie n d a ls o wa s t au gh t ho w t o r ec og n i ze a nd t re a t s ymp t om s o f
h yp o g l yc em i a. O f t en , p a ti e n ts i g no r e e a rl y wa r n i ng s ymp t oms an d p r o g re ss t o a p o in t
t h a t t h e y l os e th e j ud gme n t n e ed e d t o t r ea t th e co n di t io n . I f M. M. h a s n ot ye t b ec om e
c om b at i ve , a “ qu ic k ” - ac t in g c a r bo h yd ra t e s ou r ce s h ou l d b e o ff e r ed . If he h a s l os t
c o ns ci ou sn es s , g lu ca g on s ho u ld be in je c te d .
A l l o f th es e m an e u ve rs di m in is he d th e f r e qu en c y o f M. M. ' s s e ve re h yp og l yc em ic r ea c ti on s . O n
t h e wh o le , h is bl o od gl uco s e co n ce n tr a ti o ns we r e m ai n ta i n e d b el o w 1 8 0 mg / d L, an d h e
r e m ai ne d re l at i vel y f r e e o f h ype r g l yc em ic s ym p tom s . M. M. ' s A 1 C u si ng t his in su l in r eg im en wa s
8 . 0 %.
Diabetic Ketoacidosis
J . L . , a 2 5 - ye a r - o l d , 6 0 -kg w o m an w i t h a n 8 - ye a r h i s t o r y o f t yp e 1 d i ab et e s , i s m o d e ra t e l y
w e ll c on t r o l le d o n 2 4 un i t s La n tu s pl u s p r e -me a l do s es o f i ns u l in l isp r o . H e r fa m il y
b r i n g s h e r to t he E D , w h e r e s h e c o mp l ai n s o f a b d om i n al t en d e r ne ss , n a u se a , a n d
vo m i t i n g . Ac c o r d i n g t o h e r f am i l y, J . L . w as w e ll u n t il 2 d a ys a g o w he n s h e aw o ke w i t h
n a u se a , vom i t i ng , di a r r h e a , a n d c hi l l s. B ec a use s he w a s u n ab l e t o e a t, s h e o mi t t e d h e r
u s u al m o rn i n g d o se o f i n s u li n . He r g as t r o in t es t i n al ( G I ) s ym p t o m s p ro g r e ss e d , a nd s he
w a s b r o ug h t to t he E D w h en sh e be ca m e l e t har g i c .
P h ys i c a l e xa m in a t io n re ve a l s a n il l - ap p ea r i n g w o ma n w ho i s l e th a r g ic b u t r es p on s i ve .
H e r t e mp e r a tu r e is 37 °C . S k i n t u r g o r i s p o o r , m u c ou s m e mb r a n es a re d r y, a n d h e r
e ye b a l l s a r e s h ru n ke n a n d s o f t . J . L. ' s l u ng s ar e c l ea r , b u t r es p i ra t i on s a re d ee p a n d h e r
b r e a t h h as a f ru i t y o d o r . C a r d i ac ex am i n at i o n i s w i t h in no r m a l l im i t s .
I n t h e s up i ne p os i t io n , J . L . 's pu l s e r a t e i s 1 15 b e a t s/ m in ( no r m a l, 60 to 1 00 ) an d he r B P is
1 0 5 /6 0 m m Hg ( n o rm a l, 8 5 t o 1 30 ) . I n t he up r i gh t p os i t i on , he r p ul s e in c r e as e d t o 14 0
b e a t s/ m in , an d h e r B P d r o p p ed t o 8 5 /4 0 m m Hg . T he r e is mi l d , d i f fu se t e nd e r ne s s o ve r
h e r a bd o me n .
L a b o r at o r y r e s u l t s on ad m i ss i o n d is c l os e d t h e f o l l ow in g : b l o od g lu c os e , 7 5 0 m g /d L ;
s o d i um ( N a) , 14 8 m E q /L ( n o r ma l , 1 35 t o 1 47 ) ; p o t a ss i um ( K ) , 5 . 4 m E q/ L ( n o rm a l, 3 .5 t o
5 . 0 ) ; c h lo r i n e ( C l ) , 1 06 m E q / L ( n o r ma l , 9 5 t o 10 5 ) ; H C O 3 , 6 m E q / L ( n or m a l , 2 2 to 28 ) ; S r C r ,
2 . 0 m g / dL ( no r m a l, 0. 6 t o 1 .2 ) ; h e m og l o bi n ( H gb ) , 14 . 7 g / d L ( n o rm a l, 11 . 5 to 15 . 5 ) ;
h e m a to c r i t ( H c t ) , 4 9 % ( n o r m a l, 33 % t o 4 3 %) ; w h i t e bl o od ce l l (W B C ) co u n t , 1 5 ,0 0 0/ mm 3
( n o r m al , 3, 2 00 t o 9 ,8 0 0 ) w i th 3 % b a n d s ( n o rm a l, 3 t o 5 %) , 7 0 % p o l ym o r p h o n uc l ea r
n e u t r o ph i ls ( n o rm a l, 54 t o 62 %) , a n d 2 7 % l ym p h o c yt e s ( n o r ma l , 2 5 to 3 3 %) ; s e r u m
k e t o ne s w e re mo d e ra t e a t 1 :1 0 d i l ut i o n ( n o r mal , n eg a t i ve ) . T he u r i na lys i s s h ow e d 2 %
g l u c os e (n o r ma l , 0 ) ; mo d e r a te ke t o ne s (n o r ma l , 0) ; p H , 5 .5 ( n o rm a l, 4 . 6 to 8 ) ; a nd a
s p e ci f i c g r a vi t y o f 1 . 0 29 ( n o rm a l , 1 .0 2 0 t o 1 . 025 ) ; t h e r e w e r e n o W B C s, R B C s , ba c te r i a , o r
c a s ts . Ar t e r i a l b l o od gas ( AB G ) r e s u l t s w e r e as f o l low s : p H , 7 .0 5 ( n o rm a l , 7 . 36 t o 7 .4 4 ) ;
P C O 2 , 2 0 m m Hg ( no r ma l , 35 t o 4 5) ; P O 2 , 1 20 m m H g ( n o r ma l , 9 0 t o 10 0 ) . W h a t s up p o r t s
t h e d ia g no s is o f D K A i n J . L. ?
[ S I un i ts : b l oo d g lu c os e, 4 1 . 6 mm ol / L ; N a , 1 48 mm o l/ L ; K , 5. 4 m mo l /L ; Cl , 1 0 6 mm ol / L ; H C O 3 ,
6 mm ol / L ; S r C r , 1 7 6. 8 µm o l/ L ; Hg b , 1 47 g/ L ; Hc t, 0 . 49 ; W BC co un t , 1 5 × 1 0 9 /L wi t h 0. 0 3
b a n ds ; p ol ym o rp h on uc lea r n eu t ro p hi ls , 0 . 70 ; l ymp h oc yt e s, 0. 2 7; P C O 2 , 2 .6 k Pa ; P O 2 , 1 6. 0 k P a]
Th e f a ct th a t J .L . ha s t yp e 1 d ia b et es pu t s h er at r is k f o r d e ve lo pi n g ke t oa c id os is . An ab so l ut e
o r r el a ti ve in su l in de f ic ien c y p ro mo t es li po l ysi s an d m e ta b ol is m o f f r ee f att y a c id s t o β h yd r o xyb u t yr a t e , ac et o ac e ti c a ci d , a nd ac et o ne in t he li ve r . E xc e ss g l uc ag o n e n ha nc es
g l uc o ne og e ne si s a nd imp a i rs pe r ip h er a l ke t on e ut i li za t i on . St r es s c an c o nt r i bu t e t o th e
d e ve l op me n t o f d ia b et ic k e to ac i do si s ( D K A ) b y s ti m ul a ti ng r el e as e o f i ns ul i n c ou n te r - r eg ul a to r y
h o r mo ne s s uc h a s g lu cag o n , ca t ec h ol am in es , gl uc oc o r ti co i ds , a nd g ro wt h h o rm o ne . Co mm on
s t r es s f ac to r s i nc lu d e i nfe c ti o n, p re g na nc y, pa n cre a t it is , t ra um a , h yp e rt h yr o i di sm , a n d ac u te
MI .
J . L . p re s en t ed wi t h s ym pt o ms of na us e a, vo mi t ing , di a r rh e a, an d c hi l ls , an d th es e a r e
s u gg es t i ve o f a n a cu t e vir a l g a st r oe n te r i ti s. P a ti en t s s uc h as J. L . c omm o nl y d is co n ti n ue th e i r
i n su li n i n th is s e tt i ng , wh i c h f u rt h e r p re d is po se s th e m t o t h e d e vel op m en t o f D K A (s ee
Q u e s ti o n 3 1 ) . Ta b le 50 - 26 l is ts pa t ie n t e du ca t io n p o in t s wi t h r eg a r d t o D KA .
A s il lu s t ra t ed b y J . L. , p at i e nt s wi t h D K A p re se n t wi t h m od e r at e to hi gh ser u m g l uc os e
c o nc en t r at i on s se c on da ry t o d ec r ea se d p e ri p he r al u ti li za t io n an d i nc r ea sed h ep a ti c p r od uc t io n
( Ta b l e 5 0 - 27 ) . Th is i nc r ea s es s e ru m o sm ol al i t y, wh i c h in i ti al l y sh i ft s f lu i d f r om t he in t ra c el lu l ar
t o t he i n t ra va sc u la r c omp a r tm e nt . W hen gl uc o se c o nc en t r at i on s e xc e e d th e r en al t hr es h ol d ,
o sm o ti c d iu r es is en su e s a n d wa t e r, so di um , po t as si um , an d o t he r el ec t ro lyt e s a re de pl e te d .
J . L . a ls o h as l os t fl ui d an d el ec t r ol yt es f ro m vomi t i ng an d d ia r r he a . E ven tu a ll y, as lo ss es
e xc e e d in p ut , th e p a ti e nt b ec om e s d eh yd r a te d ( d ry m u co us m em b r an es ; d ry s k in ; s o ft ,
s h r un ke n e ye b al ls ; i nc r ea s ed he ma t oc r it ) an d i n tr a va sc u la r vo lu me be com es de p le t ed
( o r t ho s ta t ic B P a nd pu lse ch a ng es ) .
E vi d e nc e o f e xc e s si ve ke t o ne p ro du c ti on in J. L . in c lu d es k e to nu r i a, k e to ne m ia , a n d t he
c h a ra ct e ri s ti c f r ui t y od o r o f ac et o ne on th e b r e ath . E le va t ed le ve ls o f t hes e o r g an ic ac id s
i n c re as e t h e a ni on ga p an d de c re as e t h e p H an d c a r bo na t e l e ve l s . Th e r es p i ra t or y r a t e is
i n c re as ed t o co mp e ns a te f o r th e m et a bo li c a ci do si s l e ad in g to h ype r ca pn ia ( se e Ta bl e 5 0 2 6 ) . 92 , 11 9
Treatment
H ow s h o ul d J. L . b e t rea t e d ?
Tr e a t m en t o f pa t ie n ts wi th D K A is aim e d a t c o rr e ct i o n o f i nt r a vas c ul a r vo l um e , d eh yd r a ti o n,
f l u id an d e le c t ro l yt e lo sse s , a nd h yp er os m ol a ri t y ( h yp e r gl yc em ia ) ( Ta b le 50 - 2 8 ).
Table 50-26 Diabetic Ketoacidosis (DKA): Patient Education
Definition: DKA occurs when the body has insufficient insulin.
Questions to Ask:
1. Has insulin use been discontinued or a dose skipped for any reason?
2. If an insulin pump is being used, is the tubing clogged or twisted? Has the catheter
become dislodged?
3. Has the insulin being used lost its activity? Is the bottle of regular insulin cloudy?
Does the bottle of NPH appear frosty?
4. Have insulin requirements increased due to illness or other forms of stress
(infection, pregnancy, pancreatitis, trauma, hyperthyroidism, or myocardial
infarction)?
What to Look For:
1. Signs and symptoms of hyperglycemia: thirst, excessive urination, fatigue, blurred
vision, consistently elevated blood glucose concentrations (>300 mg/dL)
2. Signs of acidosis: fruity breath odor, deep and difficult breathing
3. Signs of dehydration: dry mouth; warm, dry skin; fatigue
4. Others: stomach pain, nausea, vomiting, loss of appetite
What to Do:
1.
2.
3.
4.
5.
6.
Review “Sick Day Management” (Table 50-24)
Test blood glucose four or more times daily
Test urine for ketones when blood glucose concentration is > 300 mg/dL
Drink plenty of fluids (water, clear soups)
Continue taking insulin dose
Contact physician immediately
Table 50-27 Common Laboratory Abnormalities in DKA
Glucose
> 250 mg/dL
Serum osmolarity
Variable, can be >320 in presence of coma
Sodium
Low, normal, or higha
Potassium
Normal or high
Ketones
Present in urine and blood
pH
Mild: 7.25–7.30
Moderate: 7.00–7.24
Severe: < 7.00
Bicarbonate
Mild: 15–18
Moderate: 10–15
Severe: <10
WBC count
15,000–40,000 cells/mm even without evidence of infection
a
Total body sodium is always low.
DKA, diabetic ketoacidosis; WBC, white blood cell.
P . 5 0 -4 5
Fluids
R a p i d co r r ec t io n o f f l ui d l o ss i s m os t c ru ci a l. Th e u su a l f lu i d d ef ic i t a pp r oxi m a t e s 6 to 10 L o r
1 0 % o f b o d y we i gh t i n mo s t p a ti en t s wi t h D K A . I n t h e a bs en c e o f ca r d ia c c om p r om is e,
h yp e r na t r em ia o r si g ni f ica n t re n al d ys f un c ti on , iso t o ni c sa l in e (0 . 9% N a Cl) s ho u ld be
u s ed . 92 , 11 9
J . L . h as e vi d en ce of si gni f ic a nt de h yd r at i on an d in t r a vas cu l a r vo l um e d epl e t io n . A r ou gh
c a lc ul a ti on in d ic at e s t ha t a p p ro xi m a t el y 6 t o 7 L wi l l b e n ee d ed ( 10 % o f bo d y we i g h t ).
Typ i c a l l y, f lu i ds a r e re p la c ed at t he r at e o f 1 5 to 2 0 m L /k g /h r ; d u ri n g t he fi r s t h ou r ( ~1 to 1. 5 L
i n th e a ve r a ge ad ul t ) . The su bs e qu e nt ch oi ce f o r f l u id re p la ce me n t d ep e nd s o n th e p a ti en t ' s
s t a te of h yd ra t io n , se r um e l ec t ro l yt e l e vel s, an d ur i n a r y o u tp u t . I n g en e r al , 0 . 45 % Na C L
i n f us ed at a r a te o f 4 to 1 4 m L /k g /h r i s a p pr o p ri at e if t he c o r re c te d s e ru m s od i um i s n o rm al o r
e l e va te d . I f t h e c or r ec t ed se r um so di um is lo w, 0. 9 % Na C l i s p r e fe r r ed . 92 , 1 1 9 W hen s e ru m
g l uc os e c on ce n t ra t io ns ap p r oa ch 25 0 to 30 0 m g/ dL , so lu t io ns sh ou l d b e ch a n ge d t o 5 %
g l uc os e i n h a lf - no r ma l sa l in e . Gl uc o se i s a d de d to p r e ven t h yp o gl yc em ia a n d c e re b ra l e d em a
t h a t c an occ u r i f th e o smo l al i t y is re du c ed to o ra pi d l y. Th e u se of de xt r o s e a ls o a l lo ws f o r
c o nt i nu e d i ns ul in ad mi n is t r at i on th a t i s r e qu i re d to r es o l ve t he ke t oa ci do sis (s e e Qu es t io n 4 2 ) .
Th e s e re co mm en d at i on s f o r fl u id r ep la ce me n t m us t be ad ju s te d i n t h e e lde r l y o r t h os e wi t h
c om p r om is ed r en al o r myo c a r di al f un ct i on . I n th es e p a ti e nt s , f lu i d a dm in is t r at i on m u st be
t i t r at e d a ga i ns t ce n t ra l ve n o us p r es su r e . 9 2 , 1 1 9
Table 50-28 Management of Diabetic Ketoacidosis
Fluid Administration
Use normal saline unless patient has cardiac compromise, is hypernatremic (Na > 150
mEq/L), or has significant renal dysfunction
If perfusion is adequate (e.g., normal pulse and blood pressure, good skin turgor) and Na
>150 mEq/L, use half normal saline.
Rate: 15–20 mL/kg body weight during first hour, then 4–14 mL/kg/hr
Insulin
Continuous IV infusion of regular insulin is preferred. Use IM route only if infusion is not
available.
Loading Dose: 0.15 U/kg IV or 20 U IM
Maintenance Dose: 0.1 U/kg/hr IV or 5–10 U/hr IM
If no change in blood glucose level after 1 hr, double infusion rate.
Once blood glucose <250 mg/dL, reduce infusion rate and change fluid to 5% dextrose (do
not stop insulin infusion).
When SC insulin can be initiated, administer dose 30 min before discontinuing IV infusion.
Potassium
Add 20–40 mEq to IV fluids except in patients with chronic renal failure, no urine output,
or initial potassium level >5.5mEq/L.
Phosphate
Initiate if level <1 mg/dL. Use potassium phosphate salt, 20–30 mEq added to replacement
fluid. Rarely needed.
Bicarbonate
Replacement is controversial and may be dangerous.
For adults with pH <6.9, 100 mmol sodium bicarbonate may be added to 400 mL sterile
water and given at a rate of 200 mL/hr. For adults with pH of 6.9–7.0, 50 mmol sodium
bicarbonate diluted in 200 mL sterile water can be infused at a rate of 200 mL/hr. No
bicarbonate is necessary if pH >7.0.
Sodium
To t a l bo d y so di um us u al ly i s de pl e te d b y 7 to 10 m E q /k g o f b o d y we i gh t in p at i en ts wi t h D K A .
I n as se ss in g s e ru m so d iu m i n th es e p a ti en t s, it is im po r t an t to r em em be r t h a t f al se lo w va l u es
( i . e ., ps eu d oh yp o na t r em ia ) ma y b e t h e r es ul t of hyp e r g l yce mi a a n d h yp er tr i g l yce r id em i a. A
c o r re c te d s od i um val u e m a y be ob t ai n ed b y ad din g 1. 6 to 2 m Eq / L t o t h e o b se r ve d val u e f o r
e ve r y 1 0 0 mg / dL gl uc o se > 2 00 mg / dL . 12 0 So di um i s r e pl ac e d a de qu a te l y wi t h n o rm a l
s a li ne . 92 , 1 19
P . 5 0 -4 6
Potassium
P o t as si um ba l an ce is a l te r e d m ar k ed l y i n pa ti e nts wi t h D K A b ec a us e o f co m bi n ed ur i na r y a nd
G I l os se s . I n va ri a bl y, to ta l po t ass i um i s d ep l et e d; h o we ve r , t he s e r um p o ta ss i um c o nc en t ra t io n
m a y be hi g h, no r ma l , o r lo w, d e p en d in g o n t h e d eg r e e o f a ci d os is a n d vo lu m e co n t ra c ti on .
U s u al po t as si um de f ic it s i n t h is s i tu a ti on a ve ra g e 3 t o 5 m E q/ kg o f b od y w e i gh t , a l th o ug h t h e y
m a y be as hi g h as 10 mE q / kg . 92 , 11 9
Th u s , J . L. wi l l n e ed ap p ro xi m a t e l y 2 0 0 t o 3 50 m Eq o f p o ta ss iu m t o r e pl e nis h h e r b o d y s t or e s,
a ss u mi ng he r no r ma l we ig h t i s 7 0 k g. I n p at ie n ts wh o s e in i ti al se r um po t as si um co nc e nt r a ti on s
a r e el e va te d ( > 5 .5 m E q /L ) , po t as si um s u pp le me nt a t io n i s wi t h h el d fo r th e f i r st ho u r o r un t il
s e r um l e ve ls b e g i n t o d ro p . An ad e qu a te u ri ne ou t p ut al so sh ou l d b e e sta b li sh e d b e fo r e
p o t ass i um s u pp le me n ts a r e i n it i at e d; ho we ve r , a l o w s e r um p o ta ss iu m (< 3. 3 mE q / L) in t he fa ce
o f p ro n ou nc e d ac i do si s su g g es ts s e ve r e p ot as si um de p le t io n re qu i ri n g e ar l y, a gg r es si ve
t h e r a p y t o p r e ven t l i fe - t hr e a t en in g h yp o ka le mi a du r i ng t re a tm en t . Th e l at te r ca n o cc u r f r om
d i lu t io n , c on t in ue d u r i na ry l o ss es , c o r re ct i on of ac i do si s, an d i ns u li n -m ed ia t e d ce l lu la r up t ak e .
I n t he se c as es , in i ti al I V s o lu t io ns s h ou l d co n ta i n K C l 2 0 t o 3 0 m E q/ L .
J . L . 's ad mi ss io n l a bo r at or y d a t a r e ve al a sl i gh t l y e l e va te d S r Cr ( mo st li ke ly p r e r en a l
a zo t em i a ). Th is , in c o nj un c ti o n wi t h a h ig h - no r mal se r um po t as si um c o nc en t r a ti o n, we i g hs i n
f a vo r of wi t h h ol di n g p ot as si um un t il se r um l e ve ls b e gi n to de cl in e an d u r ine o ut p ut in c re as es .
P o t as si um le ve ls ge n e ral l y b eg in t o d ec r ea se in 1 t o 2 ho u rs , b u t i f t h e pa t i en t i s g i ven
b i ca r bo n at e , a de cl in e ma y o cc u r m or e ra p id l y. On c e p ot a ss iu m l e vel s b eg i n t o f a ll , 2 0 to 40
m E q s ho u ld be ad d ed to e a ch li t e r o f f lu i d ( 2 /3 KC l a n d 1/ 3 K P O 4 ).
Phosphate
Th e n e ed fo r ph os p ha t e i n th e t r e at me n t o f D K A is co n t ro ve r si al . Ph os p hat e is l o st as th e
r e s ul t o f i nc r e as ed ti ss ue ca t ab o li sm , i mp ai r e d ce l lu l a r u pt ak e , a nd en h an c ed r en al e xc r e t io n .
L i ke ot h e r e le ct r ol yt e s, se r u m l e vel s i ni ti a ll y ma y a p p ea r n o rm a l e ve n t ho ug h bo d y st o re s a r e
d e pl e te d . Pr o fo u nd h ypop h os p ha t em ia c a n d ec r ea s e ca r d ia c o ut p ut , al t er m en t al st a tu s , a nd
p r o du ce t iss u e h yp o xi a an d he mo l ysi s. P r os pe c ti ve , r an d om i zed s t ud i es ha ve sh o wn n o
p a r ti c ul a r a d van t ag e o f p h os p ha t e t h e r a p y i n t h e t r e at me n t o f D K A. 9 2 , 1 19 I n f ac t , o ve r ze al o us
r e p la ce me n t c an r es ul t in h yp om ag n es em ia o r h yp o ca lc em i a. N e ve rt h el ess , if ph os p ha t e
c o nc en t r at i on s d r op to 1 m g /d L o r le ss , 2 0 t o 3 0 m E q /L po t as si um ph os p ha t e c an be ad d ed t o
t h e re p la ce me n t f lu i ds .
Insulin
W h a t i s an ap p r o p r ia t e i n s u li n do s e a nd r o u te o f a dm i n is t r a t io n fo r J .L . ?
U n l es s t h e e pi so de o f DK A i s mi l d ( p H = 7 .2 5 t o 7 . 3 0 ), r eg ul a r i ns u li n b y c o nt i nu o us i n fu si o n is
t h e tr e at me n t o f c ho ic e . O n c e h yp ok a le mi a i s e xc l u de d ( K + < 3 .3 m E q /L ) , an i nt r a ve no us bo lu s
o f 0 .1 5 u ni t s/ kg f ol lo we d b y a c o nt i nu ou s i n fu si on a t a do se of 0 .1 un i t/ kg p e r h ou r s h ou ld b e
a d mi ni s te r ed . W he n t he p l as ma gl uc os e re ac h es 2 5 0 m g/ d L, t he in su li n i nf u si o n ma y b e
d e c re as e d t o 0 .0 5 to 0. 1 u n it s /k g p er h ou r . Thi s is t yp ic al l y wh e n t h e r e pla c em en t fl ui d i s
c h an g ed to D 5 W . A t t h is p o in t , t h e r a te o f i ns ul in a d mi ni s t ra ti o n o r th e c onc e nt r a ti o n o f
d e xt r o s e i s a dj us t ed t o m a in t ai n t h e g lu co se va lu e at a ro u nd 25 0 m g/ d L u n t il th e a ci d os is i s
r e s ol ve d . 9 2 , 1 1 9
Th u s , fo r J . L ., an I V b ol us do se o f 9 u n it s f o ll o wed b y an in f us io n o f 6 U / ho u r wo u ld be
a p p ro p r ia t e. Th e i ns u li n s h ou l d b e i nf us e d se p a ra t e l y fr om t he fl u id s b ei ng us e d t o r e pl ac e
vo l u me s o th a t i ts ra t e ca n be ad j us te d i n de pe n de n t l y. A so lu t io n wi t h a n i n su li n c on c en t ra t io n
o f 0 .1 U /m L c an be ob t ain e d b y a dd i ng 50 un i ts of r e gu l ar in su l in to 50 0 m L o f no rm a l s al in e . I f
a d os e o f 0 . 1 U / kg is u sed , t he i n f us io n r a te is equ i va le n t t o th e p a ti en t ' s we i g h t in k g (i n J . L. ,
6 0 m L /h o u r) . I f J. L . 's pl as ma gl uc o se c o nc en t r at io n r em ai ns un ch a ng ed af t e r 2 ho u rs , th e
i n f us io n ra t e sh o ul d b e do u bl e d. A s n ot e d p r e vio us l y, as t h e g lu co se co nce n t r at i on fa ll s t o 2 5 0
t o 30 0 m g /d L , t he in su l in i n fu si o n r a te s h ou l d b e d e c re as e d a nd a 5 % d e xt r o se so lu t io n s ho u ld
b e in st i tu t ed .
Sodium Bicarbonate
J . L . w as t r ea t ed w i t h f lu i d s , e le c t r o l yt e s , a n d i n s u li n a s di s cu s se d in p r e vi o u s q u es t i on s .
L a b o r at o r y a n d c l in i ca l d a t a 4 ho u r s a f t e r t h e ra p y a r e a s f ol l ow s : p H , 7 . 1 ; b l oo d gl u co s e,
4 0 0 m g /d L ; K , 3 .8 m E q/L ; S r C r , 3 . 1 mg / dL ; a n d s e r um ke t o ne s s t r o n gly p o s i t i ve a t a 1 :4 0
d i l u t io n . He r B P w as 1 20 / 7 0 m m H g w i t h n o o r th o s t a ti c c h an g es . U r i ne o u tp u t o ve r th e
l a s t 3 h ou r s h a s b ee n 50 0 mL . B ec a us e s e r um k e t o ne s h a ve i nc r e as e d, s h ou l d J . L.
r e c e i ve m o r e i n su l i n? S h o u l d s he r e ce i ve bi ca r b o n at e th e r a p y?
[ S I un i ts : b l oo d g lu c os e, 2 2 m mo l /L ; K , 3 .8 mm ol /L ; S r C r , 2 74 µ mo l /L ]
Th e a ss um p ti on t ha t k e to s is i s wo r se in J . L . is inc o r re c t. I n D K A , l o w l e vel s o f i n su li n a n d
e l e va te d g l uc ag on le ve ls p r om o te th e m e ta b ol is m o f f re e f a tt y a ci ds in th e l i ve r t o a ce t oa c et a te
a n d β -h yd r o xyb u t yr a t e . Th e s t an da r d n i t ro p ru ss id e r ea ct i on te s t f o r ke t on e s me a su r es o n l y
a c et o a c e ta t e, e ven th o ug h β - h yd ro xyb u t yr a t e is th e m o r e im p or t an t k e to ne . Th e c o n ve rs io n o f
a c et o ac e ti c ac i d t o β - h yd r o xyb u t yr a t e is c o up le d c lo se l y wi t h th e N A D H :N A D r a t io . If t hi s r a ti o
i s h i gh ( as i n t h e p r es enc e o f al co ho l ) s o m uc h β - h yd r o xyb u t yr a t e m a y b e f o rm e d t ha t
a c et o ac e ta t e is vi r tu a ll y u n d et ec t ab l e; th u s, th e ab s en ce o f ke t on es in th e s e ru m d oe s n o t r ul e
o u t k e to ac id o si s.
C o n ve r se l y, t re a tm en t wit h in su l in be gi ns t o su p pr e ss li p ol ys is a n d f a tt y ac i d o xi d a t io n ; N A D is
r e g en e r at e d sh i ft i ng th e r e a ct i on ba ck i n fa vo r o f a c et o ac e ta t e. 9 2 , 1 19 Th us , e ven th o ug h t h e re
a p p ea rs t o b e h ig he r co nc e nt r a ti o ns o f k e to n es i n t h e s er u m, J . L . 's de cl in in g bl oo d gl uc os e
c o nc en t r at i on , i mp r o ve d b i ca r bo n at e c o nc en t ra t ion s , a nd im p ro ve d a ci d - ba s e a nd
c a r di o vas cu l ar r es po ns es in d ic at e th a t sh e i s r esp o n di ng ap p r op r ia t el y. Th e r e fo r e, no ch a ng e
i n th e i ns u li n d os e i s i ndi c at e d. I t is i m po r t an t to e m ph as i ze t h a t t he gl uco s e co n ce n tr a ti o ns
n o r ma li ze be f o re ke t on es ( 4 t o 6 ho u rs ve rs us 6 t o 12 ho u rs ) be ca us e th e l a tt e r a r e
m e ta b ol i ze d mo r e s lo wl y. F o r t hi s re as o n, it is i mp o r t an t t o c o nt in u e i ns ul in t o m ai n ta in
s u pp r es si o n o f l ip ol ys is u n t il pl as ma an d u r in e ke t o ne s h a ve c le a re d .
Th e u se o f so d iu m b ic a rb o n at e i n p a ti e nt s wi t h DK A h as be e n co n t ro ve r sia l . 92 , 11 9 Mo s t
i n ve st i ga t o rs d is co u r ag e i t s r ou t in e u se , r es er vi ng i t f o r p a ti en t s wi t h se ve r e ac id em ia ( p H
< 7 . 0 ) o r t h os e i n cl i ni ca l s ho ck . C om a is c o r r el ate d m os t c l os el y t o b lo o d g l uc os e
c o nc en t r at i on s ( > 70 0 m g/ d L ) a n d h yp e ro sm ol al i t y ( c al cu l at e d os mo l al i t y >3 4 0 m O sm /k g ) . 9 2 I n
a r a nd om i zed , p ro sp ec t ive s t ud y, bi ca r b on a te did n ot a ff ec t re co ve r y i n p a t ie n ts wi t h s e ve re
D K A ( a r t er i al p H, 6 .9 to 7 . 1 4 ). 1 21 Th us , e ven tho u g h J. L . ' s ac i do si s se em e d se ve r e o n
a d mi ss io n (p H , 7 . 05 ; bi ca r b on a te , 6 m Eq / L; K us sm a ul r es pi r at i on s ), bi ca rb o n at e wa s n o t
a d mi ni s te r ed . It is ap pa re n t th a t wi t h fl u id an d i ns u li n t h e ra p y al on e , h e r a c id os is is b e gi n ni ng
t o im p ro ve .
P . 5 0 -4 7
W h a t i s th e ex p ec t ed co u r s e o f D K A i n J .L . ?
A f t e r 3 L o f f l ui d a nd a co n st a nt in su l in in f us io n o f 6 U/ h ou r fo r 3 h ou r s, J . L . 's gl uc os e
c o nc en t r at i on ha d d r op pe d t o 50 0 m g /d L a n d sh e h a d n o o r th os t a ti c B P ch a n ge s, r ef l ec ti n g
r e c o ve r y f r om he r vo lu me - d ep l et e d s ta t us . P o ta ss i um (4 0 m E q/ L ) wa s a dd e d t o h e r f l ui ds ,
wh i c h we r e ad mi n is te r e d a t a r ed uc e d r a te o f 3 00 m L /h ou r .
Th r e e h ou rs la t e r, t he glu c os e c on ce n t ra ti o n h ad d r o pp ed t o 3 50 m g /d L an d he r p H h ad
i n c re as ed t o 7 .2 1 . Th e se r u m p ot as si um r em ai n ed l o w - n o rm al at 3 .4 m E q/ L , an d s er u m so d iu m
i n c re as ed t o 1 51 m E q /L . I n vi e w o f t h es e ch a ng es , th e I V in f us io n fl ui d wa s c ha n ge d to ha l f n o r ma l s al in e wi t h 5 % de xt r o s e t o wh i c h 4 0 m Eq/ L o f p ot as si um wa s ad de d . Th e r a te wa s
s l o we d t o 25 0 m L/ h ou r , a n d t h e i ns ul in in f us io n wa s d e cr e as ed t o 4 U /h ou r .
F o u r h o ur s l a te r (1 0 h o ur s af t e r a dm is si on ) , th e b l oo d g l uc os e wa s 2 35 m g /d L a n d t he se r um
p o t ass i um wa s 3 . 5 m Eq /d L . Th e I V fl u id s w e r e cha n g ed to 5% de xt r o s e wit h 40 m Eq / L o f K C l ,
a d mi ni s te r ed a t a ra t e o f 2 5 0 mL / ho u r , a nd t he reg u la r in su l in in f us io n was de c re as e d f r om 6
t o 2 U/ h ou r . J .L . c o nt i nue d to im p ro ve o ve r t he ne xt 1 2 h ou r s , a nd s h e b eg a n t ak i ng fu l l o r al
l i qu i ds b y t h e se co n d h os p it a l d a y. A t th a t t im e , h e r I V i nf us i on r at e wa s d e c re as e d t o 2 00
m L /h o u r b ut he r in su li n in f us i on wa s c o nt i nu ed .
A p p r o xi m a te l y 24 ho u rs a f t e r a dm is si on , J . L. ' s b lo o d g lu c os e co nc e nt r a tio n wa s 17 5 m g/ d L,
p o t ass i um wa s 4 . 6 m Eq /L , an d s od i um wa s 1 4 4 m E q /L . Th e re we r e no ke t o ne s i n t he pl as ma .
Th e u r in e c o nt a in ed 1% g l uc os e a n d mo d e ra t e am o un ts o f ke t on es . I V f lui d s we r e d isc o nt i nu e d
a n d re gu l a r i ns ul in wa s a d mi ni s te r ed su bc u ta n eou s l y 1 ho u r b e fo r e t h e i ns u li n i n fu si on wa s
d i sc on t in u ed . J .L . c o nt i nu e d t o re ce i ve re g ul a r i ns u li n s ub cu t an e ou sl y e ve r y 4 ho u rs ac co r di n g
t o a s li di n g sc al e (s ee Qu e st i on 18 ) . Th i rt y - s i x ho u r s a ft e r a dm is si o n, J. L. wa s g i ven he r us ua l
d o se of in su l in gl a rg i ne a n d i ns ul i n l is p ro an d was se n t h om e f o r f ol l o w - up i n t he cl in ic .
Treatment of Type 2 Diabetes: Oral Antidiabetic Age nts
Th i s se ct i on of th e c h ap te r a dd r es se s t he cl in ic a l p h a rm ac ol og y o f a g en ts u se d to t re a t t yp e 2
d i ab e te s . A l th o ug h t yp e 2 d ia be t es is th e m os t co mm o n f o rm of di ab e t es m e ll i tu s, it o ft e n is
d i sm iss e d a s “ mi ld ” di abe t es o r a s a “t o uc h o f d ia b e te s ” a nd hi st o ri c al l y h a s b ee n t r e at e d f a r
l e ss a g g re ss i vel y t ha n t yp e 1 d ia b et es m e ll i tu s. As de sc r ib e d i n t he in t r odu c ti o n, t he m e di ca l
c om mu n it y h as no w r e a lize d t ha t t ype 2 d ia b et es i s a se r io us co nd i ti o n t ha t mu st be ma na g ed
i n th e c on t e xt o f th e m eta b ol ic s yn d r om e . A t th e ti m e o f d ia g no si s, ma n y pe o pl e wi t h t yp e 2
d i ab e te s a l re a d y h a ve evi d e nc e o f m ac r o vas cu l ar a n d mi c ro va sc ul a r d is ea s e. Th e U K P D S
d e mo ns t r at e d t ha t im pr ove d g l yc e mi c co n t ro l wi ll r e d uc e t he on se t an d p ro g r es si on o f
m ic r o vas cu l a r co mp l ic at io n s a nd bl o od pr e ss ur e c o nt r o l wi l l al so re d uc e m ac r o vas cu l a r
c om p li ca t io ns . Th us , e ver y e f f o rt t o l o we r gl uc os e c on ce n t ra t io ns t o wa r d no r m al va lu es ,
c o nt r o l b lo od p re ss u re , an d lo we r c ho le s te r ol is im p o rt a nt to de l a y th e o ns e t o r s lo w t h e
p r o g re ss io n o f th es e c om p li ca t io ns , i mp r o ve t h e o ve r a ll qu al i t y of th e p at i e nt ' s l i fe , a n d s a ve
t h e h e al t h ca r e s ys te m m i ll io ns o f d ol la r s i n h osp i t al i za ti on co st s t o t r e at t h es e c om pl ic a ti on s .
Th e i mp o r ta nc e o f d i et , e xe r c i s e, an d o t he r li f es tyl e ch a ng es as c o r ne rs to n es in t r e a tm en t of
p e o pl e wi t h t yp e 2 di ab et e s c an n ot be o ve re mp ha s i zed . U nf o r tu na t el y, t he s e me a su r es a l on e
u s ua ll y a r e n o t su cc es sfu l in ac hi e vin g c o nt r ol f or t h e ma j o ri t y of pa t ie n ts, a nd d ru gs a re
e ve n t ua ll y r e qu i r ed .
U n t i l 1 99 5 , o nl y su l fo n ylu r e as an d i ns ul i n we r e ava i l ab l e t o t r e at t ype 2 di a be t es . Si nc e th en ,
m e t fo rm i n, α - g lu co si d ase i nh ib i to r s ( ac a r bo se and mi g li t ol ) , t h ia zo li d in ed io n es ( ro si g li t a zon e
a n d p io g li t a zon e ) , a nd no n su l fo n yl ur e a i ns ul i n sec r e ta g og ue s (r e pa g li ni d e a n d n at e gl in i de )
h a ve be e n a pp r o v ed b y th e F D A , a nd m a n y o t he r a g e nt s wi t h di f f e ri ng mec h an is ms of ac ti o n
a r e i n de ve lo pm e nt . Th es e a g en t s gi ve cl in ic i an s a n d p at i en ts mo r e c ho ice , bu t th e re is
c o ns id e ra b le c o n fu si on ab o u t wh i c h o f t h es e a gen t s t o u se in i ti al l y as m on o t he r ap y a n d h o w
t h e y sh o ul d b e u se d i n co m bi n at io n wi t h o n e a not h e r o r wi t h i ns u li n . P a tie n ts wi t h t ype 2
d i ab e te s o f te n a r e a l re ad y t a ki ng se ve r al o th e r dr u g s t o t r ea t th e ir ca r di ova s c ul a r co n di t io ns ,
d ys l ip id e mi a, h yp er t en sio n , d e p re ss io n , a nd ot h er c h ro ni c i ll n ess e s t ha t c o m e wi t h ag i ng . Th is
d o es no t a cc o un t f o r th e m an y n u t ri ti o na l , h e rb al, h om eo p at h ic re me d ie s a n d o ve r - t he -c o un t e r
( O TC ) m e d ic a ti o ns p a ti en t s o f te n s el f - p re sc ri b e. Th e r e f o re , in ou r vie w, t h e ai m sh o ul d b e t h e
s im p le st , s a fe s t r eg im e n t h a t gi ve s t h e p a ti en t the b es t g l yce mi c co n t ro l po ss i bl e .
F i g ur e 5 0 - 8 d ep ic ts t he so u r ce s o f h yp e rg l yce mi a i n p e op le wi t h t ype 2 d ia b e te s a nd th e
p r i ma r y si t e o f a ct i on fo r e ac h c la ss of ag e nt s d es c ri b ed s u bs eq u en t l y. Ta b le s 5 0 -2 9 , 5 0 -3 0 ,
a n d 5 0 -3 1 s um ma r i ze t he p ha r ma co ki n et ic s, ph ar m ac o lo g y, a n d d r ug in t er a c ti o ns o f th e o r al
a n t id ia b et ic d ru gs . Th e cl i ni ca l u se o f t he se ag e nt s in s p ec if ic si tu a ti o ns is il l us t ra t ed b y c as es
l a t er in t hi s ch a pt e r .
α-Glucosidase Inhibitors
T wo o r a l a g en ts f or t he tr e a tm e nt of t yp e 2 d i ab et e s m el li t us be lo n g t o t he α - g lu co si d as e
i n hi b it o r c la ss , a ca r bo s e ( P r e co se ) an d m ig li t ol (G l ys e t ) . A ca r b os e is a vai l ab l e i n E u ro p e u nd e r
t h e tr a de na me G l uc ob ay.
FIGURE 50-8 Sources of hyperglycemia in
type 2 diabetes and site of action of oral
antidiabetic agents. GI, gastrointestinal;
HGO, hepatic glucose output.
View Figure
Table 50-29 Oral Antidiabetic Pharmacokinetic Data149,150
Usual
Minimu
m and
Maximu
Drug (Brand
m Total
Name)
Typical Daily
Available
Dosing Dose/Ho
Tablet
Regimen w
Mean
Strengths (mg) (mg)
Divided Half-Life
Bioavailabil
Approxima ity
te
Metabolism
Duration , and
of Activity Excretion Comments
α-Glucosidase Inhibitors
Acarbose
(Precose)
25, 50, 100
mg
25–
100
mg
with
first
bite
of
eac
h
Mini
mu
m:
25
mg
TID
Max
imu
m
2.8 hr
Affect
s
absorp
tion of
compl
ex
carbo
hydrat
es in a
F=
0.5–
1.7%;
extensi
vely
metabo
lized
by GI
amylas
Titrat
e
doses
slowl
y to
avoid
GI
effect
s
Miglitol
(Glyset)
25, 50, 100
mg
mea
l.
Beg
in
with
25
mg;
↑ by
25
mg/
mea
l
ever
y 4–
8
wee
ks.
dose
is 50
mg
TID
if
<60
kg;
100
mg
TID
if
>60
kg.
25–
100
mg
with
first
bite
of
eac
h
mea
l.
Beg
in
with
25
mg;
↑ by
25
mg/
mea
l
ever
y 4–
8
wee
ks.
Mini
mu
m:
25
mg
TID
Max
imu
m:
100
mg
TID
2 hr
single
meal
es to
inactiv
e
produc
ts;
50%
excrete
d
unchan
ged in
the
feces
Affect
s
absorp
tion of
compl
ex
carbo
hydrat
es in a
single
meal
Dose
of 25
mg is
comple
tely
absorb
ed;
dose of
100
mg
50–
70%
absorb
ed;
elimina
tion by
renal
excreti
on as
unchan
ged
drug
Biguanides
Metformin
(Glucopha
ge) 500,
850 mg
Beg
in
with
500
mg
QD
or
BID
;↑
by
500
mg
QD
ever
y 1–
2
wee
ks.
0.5–
2.5 g
BID
or
TID
Plas
ma,
6.2 hr
Whol
e
blood
, 17.6
hr
6–12
hr
F=
50–
60%;
excrete
d
unchan
ged in
urine
Avoi
d in
patie
nts
with
renal
failur
e or
those
who
could
be
predi
spose
d to
lactic
acido
sis
(e.g.,
alcoh
olism
,
CHF,
sever
e
respir
atory
disor
ders,
liver
failur
e)
Metformin
extendedrelease
(Glucopha
ge XR)
500 mg
500
–
1,00
0
mg
QD
with
eve
1,50
0–
2,00
0 mg
QD
As
for
metfo
rmin,
but
activ
e
drug
24 hr
As for
metfor
min
As
for
metfo
rmin
ning
mea
l; ↑
by
500
mg
ever
y 1–
2
wee
ks.
is
releas
ed
slowl
y
Nonsulfonylurea Insulin Secretagogues
Repaglinid
e (Prandin)
0.5, 1, 2
mg
If
A1C
is
<8
%
or if
this
is
first
dru
g,
begi
n
with
0.5
mg
with
eac
h
mea
l.
For
othe
rs,
begi
n
with
1–2
mg/
0.5–
4 mg
with
each
meal
(16
mg/
day)
TID
–
QID
1 hr
Cmax
is at 1
hr;
durati
on is
appro
ximat
ely 2–
3 hr
F=
56%;
92%
metabo
lized to
inactiv
e
produc
ts by
the
liver;
8%
excrete
d as
metabo
lites
unchan
ged in
the
urine
Take
only
with
meals
. Skip
dose
if
meal
is
skipp
ed.
mea
l.
Netaglinid
e (Starlix)
60, 120
mg
120
mg
TID
1–
30
min
befo
re
mea
ls;
60
mg
TID
for
pati
ents
with
near
nor
mal
A1C
at
initi
atio
n.
60
or
120
mg
TID
1.5 hr
Onset,
20
min;
peak,
1 hr;
durati
on, 2–
4 hr
F=
73%;
metabo
lized to
inactiv
e
produc
ts
(predo
minant
ly) that
are
excrete
d in the
urine
(83%)
and
feces
(10%)
Skip
dose
if
meal
is
skipp
ed.
5/1,0
00–
20/2,
000
mg
in
two
divi
ded
dose
See
metfo
rmin
and
glybu
ride
See
metfor
min
and
glybur
ide
See
metfor
min
and
glyburi
de
See
Gluc
ovanc
e
Combination Products
Glipizide/
metformin
(Metaglip)
2.5/250
mg,
2.5/500
mg, 5/500
mg
Initi
al
ther
apy:
2.5/
250
mg
QD
2nd
line
Glyburide/
Metformin
(Glucovan
ce)b
1.25/500,
2.5/500
mg
5.0/500
mg
ther
apy:
2.5–
5/50
0
mg
BID
;↑
ever
y2
wee
ks
s
2.5/
500
mg
QD
or
BID
;↑
by
2.5/
500
mg
ever
y 1–
2
wee
ks.
7.5/1
,500
–
10/2,
000
mg
in
two
to
three
divi
ded
dose
s
with
meal
s
See
metfo
rmin
See
metfor
min
See
metfor
min
and
glyburi
de
Effec
t
shoul
d be
simil
ar to
the
two
agent
s
given
in
comb
inatio
n.
Mini
mum
dose
of
1,500
mg
metfo
rmin
is
neede
d for
effect
. No
need
to
excee
d 10
mg
glybu
ride
Metformin
/rosiglitazo
ne
(Avandam
et) 500/1
mg, 500/2
mg/ 500/4
mg
2/50
0
mg
BID
4/1,0
00
mg–
8/2,0
00
mg
in
two
divi
ded
dose
s
with
meal
s
See
metfo
rmin
and
rosigl
itazo
ne
See
rosigli
tazone
See
metfor
min
and
rosiglit
azone
Dose
titrati
on
sched
ule is
depen
dent
on
whic
h
drug
is
being
adjust
ed.
Table 50-30 Comparative Pharmacology of Antidiabetic Agents
Agent Generic Name
Brand Name
Mechanism
FDA Indications Efficacy
Insulin
Replaces or
augments
endogenous
insulin
Monotherap
y; combined
with any oral
agent
↓ A1C 4
↓ FPG∞
↓ PPG∞
↓ TG
Adverse Effects
Hypoglycemi
a, weight
gain,
lipodystrophy,
local skin
reactions.
Comments
Offers flexible
dosing to match
lifestyle and
glucose
concentrations.
Rapid onset.
Safe in
pregnancy, renal
failure, and liver
dysfunction.
Drug of choice
when patients do
not respond to
oral agents.
Insulin-Augmenting Agents
Nonsulfonylure
a secretagogues
Repaglinide
(Prandin;
NovoNorm)
Netaglinide
(Starlix)
Stimulates
insulin
secretion.
Monotherap
y; combined
with
metformin
↓ A1C
1.7%
↓ FPG 61
mg/dL
↓ PPG 48
mg/dL
Hypoglycemi
a, weight
gain.
Take only with
meals. If a meal
is skipped, skip
a dose. Flexible
dosing with
lifestyle. Safe in
renal and liver
failure. Rapid
onset.
Sulfonylureas
Various; see
Table 50-29
Stimulates
insulin
secretion. May
decrease hepatic
glucose output
and enhance
peripheral
glucose
utilization.
Monotherap
y; combined
with
metformin;
combined
with insulin
(glimepiride)
↓ A1C
1.5–1.7%
↓ FPG
50–70
mg/dL
↓ PPG 92
mg/dL
Hypoglycemi
a, especially
long-acting
agents; weight
gain (4–22
lb). Rash,
hepatotoxicity
, alcohol
intolerance,
and
hyponatremia
are rare.
Very effective
agents, but cause
hyperinsulinemi
a, which leads to
hypoglycemia
and weight gain.
Some can be
dosed once
daily. Rapid
onset of effect (1
week).
GI: flatulence,
diarrhea.
Elevations in
LFTs seen in
doses >50 mg
TID of
acarbose.
Therefore,
LFTs should
be monitored
every 3
months during
the first year
Titrate dose
slowly to
minimize GI
effects. No
hypoglycemia or
weight gain. If
used in
combination
with
hypoglycemic
agents, advise
patients to treat
hypoglycemia
Delayers of Carbohydrate Absorption
α-Glucosidase
inhibitors
Acarbose
(Precose)
Miglitol
(Glyset)
Slows
absorption of
complex
carbohydrates.
Monotherap
y; combined
with SFUs
↓ A1C
0.5–1.0%
↓ FPG
20–30
mg/dL
↓ PPG
25–50
mg/dL
of therapy and
periodically
thereafter.
Because
miglitol is not
metabolized,
monitoring of
LFTs is not
required.
with glucose
tablets because
absorption is not
inhibited as with
sucrose.
GI: cramping,
diarrhea.
Lactic
acidosis
(rare).
Titrate dose
slowly to
minimize GI
effects. No
hypoglycemia or
weight gain;
weight loss
possible. Do not
use in patients
with renal or
hepatic function
or CHF
requiring
treatment.
Insulin Sensitizers
Biguanides
Metformin
(Glucophage) ↓
Hepatic glucose
output; ↑
peripheral
glucose uptake
Monotherap
y; combined
with SFUs
↓ A1C
1.5–1.7%
↓ FPG
50–70
mg/dL
↓ PPG 83
mg/dL
↓ TG 10–
20%
↓ Total
cholestero
l 5–10%
↑ HDL
cholestero
l (slight)
Table 50-31 Pharmacokinetic Drug Interactions With Oral Antidiabetic Agents
Drugs
Comments
Pharmacokinetic Drug Interactions With Sulfonylureas
Drugs Increasing Sulfonylurea Effect
Antacids
Enhanced glyburide absorption due to increased gastric
pH. Avoid concomitant administration.
Chloramphenicol
↓ tolbutamide hepatic metabolism and ↑ t½ 2- to 3-fold.
Possible prolongation of chlorpropamide t½.
Cimetidine
↓ tolbutamide hepatic metabolism by 17% in one study.
Ranitidine had no effect.
Clofibrate
May displace sulfonylureas from proteins, ↓ insulin
resistance, ↓ renal tubular secretion of chlorpropamide.
Doxepin
Mechanism unknown. Monitor for hypoglycemia.
Fluconazole
Increased plasma concentrations. Watch for
hypoglycemia.
Gemfibrozil
Possibly due to protein displacement. May need to reduce
dose of sulfonylurea.
Halofenate
Increases serum concentrations.
Heparin
Heparin may have significantly prolonged glipizide
hypoglycemia in one unconvincing case report.
Confirmation needed.
Methandrostenolone
Enhances hypoglycemic effect. Consider nandrolone and
methenolone acetate.
Methyldopa
↑ mean tolbutamide t½ by 24% in one study.
Nonsteroidal
antiinflammatory drugs
Sulfinpyrazone and phenylbutazone ↓ tolbutamide
hepatic metabolism and ↑ t½ 2- to 3-fold. Enhanced
hypoglycemia secondary to acetohexamide (↓ renal
excretion of active metabolite) and chlorpropamide also
reported. Severe, fatal hypoglycemia can occur.
Ibuprofen, naproxen, sulindac, and tolmetin do not affect
sulfonylurea disposition.
Salicylates
Limited and indirect documentation (primarily in vitro)
that salicylates may ↑ sulfonylurea activity through
protein-binding displacement or inhibition of active renal
tubular secretion.
Sulfonamide antimicrobials
Cotrimoxazole ↓ tolbutamide metabolism and t½ by 30%
in one study. Severe hypoglycemia with glyburide and
chlopropamide reported rarely. Sulfisoxazole also rarely
associated with tolbutamide- and chlorpropamideinduced severe hypoglycemia.
Warfarin
No evidence that warfarin affects sulfonylurea
disposition; however, dicumarol ↑ tolbutamide (and
possibly chlorpropamide) t½ 3- to 4-fold, probably by ↓
hepatic metabolism. Sulfonylureas do not appear to alter
patient response to the anticoagulants. Warfarin response
should be monitored if glyburide is initiated,
discontinued, or changed in dosage.
Drugs Decreasing Sulfonylurea Effect
Alcohol
Chronic ethanol use ↑ tolbutamide hepatic metabolism 2fold. Conversely, short-term ethanol infusions ↓
tolbutamide clearance by 50%.
Rifampin
↑ tolbutamide and glyburide metabolism, thereby ↓ t½
and plasma drug concentrations.
Other Drugs
Cyclosporine
May compete with glipizide for cytochrome P450
hydroxylation. Necessitated a 20–30% dosage reduction
of cyclosporine in two case reports.
Phenytoin
Unknown effects on sulfonylureas; however, tolbutamide
transiently ↑ free phenytoin concentrations through
protein-binding displacement by approximately 45% in
one study.
Pharmacokinetic Drug Interaction With Repaglinide
Gemfibrozil
Significant ↑ in repaglinide blood levels (8-fold in AUC)
due to reduced repaglinide metabolism; do not use
concurrently.
Itraconazole/ketoconazole
↑ in repaglinide blood levels; do not use concurrently.
Pharmacokinetic Drug Interactions With Metformin
Alcohol
Potentiates the effects of metformin on lactate
metabolism. Patients should avoid excessive alcohol
intake.
Cimetidine
Increase in peak metformin plasma concentrations. May
necessitate a reduction in metformin dose. An alternate
H2 blocker is recommended.
Erythromycin
Severe cholestatic hepatitis reported when used in
combination with chlorpropamide. Monitor liver
enzymes and bilirubin or use alternate antibiotic.
Iodinated parenteral
contrast dye
Can result in acute renal failure and metformin-induced
lactic acidosis. Metformin should be withheld at least 48
hours before and 48 hours after the procedure. Reinstitute
metformin only after renal function has been determined
to be normal.
Pharmacokinetic Drug Interactions With α-Glucosidase Inhibitors
Charcoal/digestive enzyme
preparations
Intestinal adsorbents (e.g., charcoal) and digestive
enzyme preparations (e.g., amylase, pancreatin) may
reduce the effect of acarbose.
Digoxin
Serum digoxin concentrations may be reduced,
decreasing the therapeutic effects.
Propranolol
Miglitol may significantly reduce the bioavailability of
propranolol by 40%.
Ranitidine
Miglitol may significantly reduce the bioavailability of
ranitidine by 60%.
Pharmacokinetic Drug Interactions With Thiazolidinediones (Pioglitazone)
Ketoconazole
Ketoconazole appears to significantly inhibit the
metabolism of pioglitazone. Glycemic control should be
evaluated more frequently in patients taking these agents
in combination.
Oral contraceptives
Pioglitazone reduces plasma concentrations of oral
contraceptives containing ethinyl estradiol and
norethindrone. Result is a possible loss of contraception.
Watch for symptoms of estrogen deficiency (e.g., hot
flushes) in women taking estrogen hormone-replacement
therapy.
P . 5 0 -4 8
P . 5 0 -4 9
P . 5 0 -5 0
P . 5 0 -5 1
Mechanism of Action
Th e α - g l uc os id a se i n hi b it o r s r e ve rs i bl y i nh ib i t g luc os i da se s p r es en t i n th e b r us h -b o r de r of th e
m uc o sa of th e s ma ll in t es t in e . Th es e e n zyme s a re r es p on si bl e fo r th e b r ea k do wn o f c om p le x
p o l ysa cc ha r i de s a nd di ss ac c ha r id es in t o a bs o rba b le gl uc o se an d o t he r m o no sa cc ha r i de s.
Th i s r es ul ts in de l a yed di g es t io n o f c a rb o h yd ra t es an d s u bs eq ue n t g lu co se a bs o rp t io n wi t h a
l o we r i n g o f p os t p ra nd i al b l oo d g l uc os e c on ce n t rat i o ns . Thi s re du c ti on oc cu r s o n l y wh e n t he s e
a g e nt s a r e t ak en wi t h a m e al c o nt a in in g a co mp le x c a r b o h yd ra t e. 1 22 , 12 3 , 1 2 4
Pharmacokinetics
A c a r bo se is m in im a ll y a bs o r be d f r om th e G I t r ac t ; o r al bi o a vai l ab il i t y of the p a re n t co mp o un d
i s 0 . 5% t o 1 .7 % . A ca r b os e i s e xt e n s i vel y me t ab ol i ze d b y G I am yl as es to in a ct i ve m e ta b ol it es .
Th e e l im in a ti on ha l f -l i fe f o r ac a rb os e i s 2 .8 ho u rs, a lt h ou g h t he r e m a y be a l on ge r t er mi n al
h a l f- l if e .1 2 3 , 1 24 U nl ik e a c a rb os e , mi g li t ol i s a bso r b ed , do es no t u n de r go m e ta bo l ism , an d i s
e xc r e t e d u nc h an g ed in th e u ri ne wi t h an el im in a ti o n h al f - li f e o f 2 ho u rs .
Ad verse Effects
Gastrointestinal Effects
F l a tu l en ce , d i ar r h ea , a nd a bd om i na l p ai n a r e t h e m os t f r e qu e nt l y r ep o rt ed a d ve rs e e f fe ct s o f
α - g l uc os i da se in h ib i to rs , a n d i n o ne pl ac e bo -c o n tr o l le d t r i al of ac a rb os e , th e se c o mp la i nt s
we r e e xp e r i e nc e d b y 7 3.2 % , 4 3 .6 % , a nd 25 % o f th e s u bj ec t s, r es pe ct i ve l y. N o t ab l y, m an y i n
t h e p l ac eb o g r ou p a ls o co m pl ai n ed of f la t ul en ce (3 9 % ) , di a r r he a ( 2 0. 3 % ), a n d a b do mi na l
c r am ps o r d isc o mf o r t ( 8 .8 % ) . 12 5 Th es e si d e e f fec t s, wh i ch a re du e to fe rm e nt a ti o n o f
u n a bs or b ed ca r bo h yd r ate i n t he sm al l i nt e st in e , c a n b e mi n im i zed b y s l owl y t i t r a t in g th e d os e
o f ei t he r ag e nt . G I d is com f o rt us u al l y i mp r o ves wi t h c on t in u ed th e r ap y as i n du c ti on o f t he α g l uc os i da se en zym e s occ u rs in th e d is t al je j un um an d te rm i na l i le um .
Elevated Liver Function Tests
I n st u di es us in g d os es of a ca r b os e ≥ 3 00 mg / da y, a t r an si e nt in c re as e i n se r u m h ep a ti c
t r a ns am i na se s wa s r ep o rt e d . 1 2 6 Th e ma nu f ac t u rer r e co mm en ds m o ni t o ri ng h ep a ti c
t r a ns am i na se s e ve r y 3 mo n t hs fo r th e f i rs t yea r o f t h e ra p y an d p e ri o di ca l l y t h e ra f te r . 12 7 If
e l e va ti on s o f s e ru m t r ans am i na se s o cc u rs , t he do s e sh o ul d b e d ec r e as ed o r di sc on t in u ed if
e l e va ti on s p e rs is t .1 2 7 No i nc id en t s o f h ep a to t o xi c i t y ha ve be e n r ep o r te d to d at e wi t h m ig li t ol .
B e c au se m i gl i to l i s n ot m e ta b ol i ze d, it s l ac k o f e f f ec t o n h e pa t ic fu nc t ion is e xp e c te d .
Contraindications and Precautions 127 , 128
Gastrointestinal Conditions
B e c au se of t he i r p r of o un d G I e ff ec t s, ac a rb os e an d m i gl i to l a r e n ot r ec omm e nd e d f o r us e i n
p a t ie n ts wi t h m al ab s or p tio n , i n fl am ma t o r y b o we l d i se as e , o r i n te s ti na l o bs t r uc ti o n.
Renal Impairment
A c a r bo se ha s n ot be e n st u d ie d i n p a ti en t s wi t h se ve r e re n al im pa i rm en t (S r C r > 2 .0 m g /d L ) a n d
s h ou l d n ot be us ed in t he s e p at i en ts . 12 7
Hypoglycemia
P a t i en ts wh o us e a ca r bos e o r m i gl i to l i n c om bi nat i o n wi t h o th e r a nt i di a be ti c a g en ts ma y
d e ve l op h ypo gl yc em i a. Th e se r ea ct i on s sh o ul d be t r ea t ed wi t h de xt r o s e be c au se ac a rb os e m a y
l i mi t t h e a va il a bi li t y o f t he d is acc h a ri de , s uc r os e ( t a bl e s u ga r ) .
Drug Interactions
B e c au se ac a rb os e a n d m i gl i to l d el a y ca r bo h yd ra t e p as s ag e t h ro u gh th e b o we l , th e y co u ld
i n f lu en ce t he ab so r p ti on k i ne t ics o f co nc om i ta n tl y a dm i ni st e r ed dr u gs . Con ve r s el y, be ca u se
t h e ir o wn a bs o rp t io n m ay b e di mi n is he d b y c ha rco a l o r di ge s ti ve en zym e p r e pa r a ti o ns , t he y
s h ou l d n ot be ta k en c o nc om i ta n tl y wi t h t he se age n ts . Ac a rb o se an d m ig lit o l d o n o t a f fe ct t he
a b so r p ti on o f g l ybu r id e in i nd i vid u al s wi t h di a be te s . 1 2 7 , 1 28 Th e bi oa va i lab i li t y o f d ig o xi n ca n
b e r ed uc ed a nd m a y r equ i r e d os e a dj us t me n t. Mi g l i to l d ec r ea se s t h e b io ava i l ab i li t y o f
r a n it i di n e a nd pr o p ra n olo l b y 6 0 % a nd 40 % , r es pe c ti ve l y. 12 8
Efficacy
B y d e l a yin g t h e a bs o rp t io n of gl uc os e fo ll o wi n g in g es t io n o f c om pl e x c a rb o h yd ra t es an d
d i sa cc ha r id e s, th e α - gl uc os i da se in h ib i to rs ca n lo we r p o st p r an di a l p la sma g lu co se
c o nc en t r at i on s i n p at i en ts wi t h t ype 2 d ia b et es b y 2 5 to 50 m g /d L . F P G con c en t r at i on s r em a in
u n ch a ng ed o r a r e sl i gh t ly l o we r e d ( 20 to 3 0 m g / dL ) , bu t th is ef f ec t m a y be r el a t ed to
d e c re as e d gl u co se to xi c it y, wh i c h i mp r o ves in su l in se c re t io n a n d ac t io n . Me a n A 1 C va l ue s
d e cl in e b y 0 . 5% to 1% . A c a r bo se an d m ig li t ol have n o e f f ec t o n we ig h t o r l i pi d
p r o fi l es . 12 2 , 1 23 , 1 24 , 12 5
Dosage and Clinical Use
A c a r bo se c a n b e us e d as mo no t he r a p y o r in c o mb i na t io n wi t h a s u lf o n ylur e a , m et f o rm in o r
i n su li n . 1 2 7 Mi g l i t ol c a n be us e d a s mo n ot h er a p y o r in co mb i na t io n wi t h a s u lf o n ylu r ea , an d i t
h a s b ee n s t ud ie d i n c omb i na t io n wi t h i ns ul i n. 1 22 , 1 2 8 , 1 2 9 Th e r ec omm e nde d in i ti al do se o f
e i t he r dr u g is 25 mg th r ee t im es da il y, t ak en at t he b eg in n in g o f ea ch m e al , al t ho u gh e ven
l o we r d os es ha ve be e n us e d. Th e do sa g e ca n b e g r a du a ll y i nc r ea se d (e . g., 2 5 m g/ me a l) e ve r y
4 t o 8 we e ks to a ma xi m u m o f 50 m g t h r ee ti me s d a il y f o r i nd i vi du a ls ≤6 0 k g , o r 1 0 0 m g t h re e
t i me s d ai l y f or in d i vid ua ls > 60 k g . A ma xi m u m r es p on se is ob se r ve d a t 6 m o nt hs . 12 5 Pa t ie n ts
s h ou l d b e i ns t ru ct e d t o ta k e t he t ab le t at th e s t a rt o f e ac h m ea l . A ca r b os e o r m i gl i to l c an be
u s ed to t re a t p a ti e nt s wi t h t yp e 2 di ab e te s m an a ge d wi t h d i et an d e xe r c i se wh o s e A 1 C l e vel s
a r e m il d l y e l e va te d a bo ve t he t ar g et va lu e . Th e y m a y al so be us e d i n co mb i na t io n wi t h o t he r
o r a l a n ti di a be t ic a g en ts a n d i ns ul i n, pa r t ic ul a rl y wh e n p os t p ra n di al gl uc os e c on c en t ra t io ns a re
e l e va te d . A ls o s ee Q u est i o ns 5 1 , 5 7 , 5 8, 59 , 60 , a n d 6 4 .
Biguanides
Me t f o r m i n ( G l uc op h ag e ) b e lo n gs to th e b i gu a ni de c la ss of o ra l h yp o gl yc em ic ag e nt s a n d h as
b e e n a va il ab l e i n t he U nit e d St a te s s in ce 19 9 5. Me t f o rm in be ca me a vai l abl e ge ne r ic a ll y i n
2 0 0 2. P he n fo r mi n , al s o a b ig ua n id e , wa s a va il abl e in th e Un i te d St a t es un t i l 1 97 7 wh e n t he
F D A , b ec au se of ph e nf o rm i n 's ass o ci a ti on wi t h f at a l l ac t ic ac id os is , wi t hd re w i t . Th e c l in ic al
p h a rm ac ol o g y of m e t fo rm i n h as b e en e xt e n si ve ly r e vi e we d . 1 30 , 13 1 , 1 3 2 , 1 3 3
Mechanism of Action
Th e b i gu an i de s a r e d es cr i b ed mo r e ac c ur a te l y as a n ti h yp e rg l yce mi c a ge n ts . Al t ho u gh t he y
l o we r b lo o d g lu co se co nc e nt r a ti o ns i n p e op le wi t h t yp e 2 di ab e te s , t he y do n ot ca us e
P . 5 0 -5 2
h yp o g l yc em i a i n n on di a be t ic in d i vid ua ls . U nl ik e th e o ra l s ul f on yl u re as , the b ig ua n id es do no t
s t im ul a te t he re l ea se of in s ul in f r om t h e p an c re as. Th e p re ci se me ch a ni sms b y wh i ch
m e t fo rm i n l o we r s b lo o d g l uc os e c on ce n t ra t io ns re m ai n t o b e e l uc id a te d . Th e r e is e vid e nc e t ha t
m e t fo rm i n l o we r s F P G co n ce n t ra t io ns b y d ec r e as i ng gl uc o ne og e ne si s a nd t he r e fo r e h ep a ti c
g l uc os e p r od u ct i on . Me t fo r m in al so s e ems t o i m pr o ve p er i ph e ra l s e ns it i vi ty t o i ns ul in , as
i l lu s tr a te d b y e n ha nc ed g l uc os e d is p os al an d c lea r a nc e a s we l l as a r ed uc t io n i n p l asm a
i n su li n c on c en t ra t io ns . Me t f o rm in al so lo we r s pl asm a fr e e f a tt y a ci d l e vel s , a n d su b se qu e nt
o xi d a t i on , wh i ch ma y con t r ib u t e t o i ts ab il i t y to re d uc e h e pa t ic g l uc os e pr o d uc t io n a nd in c re as e
i n su li n -m e di a te d g lu co s e d is p os al in th e m us cl e . 13 4 In ad d it i on to it s e f fec t s o n F F As ,
m e t fo rm i n p r od uc es s m al l de cr e me n ts (5 % t o 1 0% ) in t ot a l ch o le st e r ol an d t ri gl yc e ri d es (1 0 %
t o 20 % ) . S ma l l i nc re m ent s or no ch a ng e i n h ig h -d e ns i t y c h ol es t er o l co nce n t r at i on s h a ve b ee n
o b se r ve d . Th e se e ff ec t s o n li pi d m e ta bo l ism as we l l a s ma n y o th e r e f fe ct s o n c lo t ti n g f ac t o rs ,
p l a te le t fu nc t io n , a nd vas cu l a r f un c ti on ha ve ge ne r a t ed in t er es t in th e p o te n t ia l f a vo r ab le
e f f ec ts o f me t fo r mi n o n ca r d io va sc ul a r d i s e as e a nd o ut co me s . 1 3 4 U n li ke th e s u lf o n ylu r ea s ,
TZ D s a n d i ns ul in , we i g ht l os s r a th e r th an we i g ht g a in is m o r e li k el y t o oc cu r wi t h m e t fo r mi n
t h e r ap y ( me a n we i g h t l os s o f 1 . 2 k g co mp a r ed wi t h 1 .7 k g i nc r e as e) . 13 5
Pharmacokinetics
A p p r o xi m a te l y 50 % t o 6 0% o f m et f o rm in is a bs o r be d f ro m t he sm al l i n te st in e . It is e l im in a te d
e n t ir e l y b y t h e ki d ne y u nc h an g ed an d h as a p la sm a h a lf - li f e o f 6 . 2 h ou r s a n d a wh o l e b lo od
h a l f- l if e o f 17 . 6 h ou r s. I t i s n o t b ou nd t o p la sm a p r o t ei ns . 13 6 , 1 3 7
Ad verse Effects
Gastrointestinal Effects
Tr a n s i en t s id e e f fe c ts i nc l ud e d ia r r h ea an d o t he r G I d is t ur b an ce s s uc h as a b do mi n al
d i sc om fo r t , m et a ll ic ta s te , na us e a, an d an o re xi a . A l t ho u gh th es e s ym pt om s c an be m i ni mi ze d
b y s lo wl y t i t r a ti ng t he dos e , p a ti en t s sh o ul d b e ad vi s ed th a t t h e y m a y e xp e r i en ce G I s i de
e f f ec ts t ha t a r e d os e re la t e d a nd s h ou l d su bs i de wi t h t im e ; me t f o rmi n s ho u ld be t ak en wi t h
f o o d t o m in im i ze G I d is tur b a nc es . In a p la ce bo - con t r ol l ed t ri a l, 5% of pa t ien t s d is co n ti nu e d
m e t fo rm i n b ec au se o f sid e ef f ec ts t ha t we r e p r edo m in a nt l y G I i n n a tu r e . R e l a ti ve to pl ac e bo ,
“ d i ge s ti ve di st u rb a nc es ” o cc u r r ed i n 28 % ver s us 1 5 % o f p a ti e nt s , a nd di ar r h e a wa s t he mo st
c om mo n c om p la in t (1 5 % ve r s us 5% ) . Al so se e Que s ti o n 5 3 .
Lactic Acidosis
Th e r i sk o f la ct ic ac id os is se co n da r y t o me t f or min is 10 t o 2 0 t im es l o we r t h an wi t h
p h e nf o rm in . 13 3 , 13 8 Un lik e p h en f o rm in , m e tf o rm in is no t m e ta b ol i zed , it do e s n ot in h ib i t
p e r ip h e ra l g lu co se o xi d at i o n, an d i t d o es no t e n ha n ce pe r ip h e ra l l ac t at e pr o d uc t io n . H o we ve r ,
i t m a y d ec r ea se c o n ve rs io n of la c ta t e t o g lu co se (d e c re as e d gl u co ne o ge n es is ) an d i nc r e as e
l a ct a te p ro d uc ti o n i n t he g u t a n d l i ve r. 1 32 , 13 3 , 1 38 C o ns eq u en t l y, m et f o rmi n ra r e l y h as be e n
a ss o ci at e d wi t h l ac ti c a ci d os is . Th e f e w p a ti e nt s i n wh o m t hi s e ve n t h as be e n re po r t ed ha d
r e n al , l i ve r , o r c a rd i or e sp i r at o r y co n t ra in d ic at i ons t o t he us e o f b i gu an i des . P at ie n ts s h ou l d b e
wa r n e d t o b r in g t h e f ol lowi n g s ym pt om s o f l ac t ic a c id os is to t he at t en t io n o f t he i r p h ys ic i an :
we a k n es s , ma l ai se , m ya lg i as , a b do mi n al di st r es s a n d h e a vy, l a bo r e d b re a th i ng ( se e Qu e st io n
66).
Contraindications and Precautions
P a t i en ts wi t h re n al im pa ir m e nt , h e pa t ic d is e as e , c o ng es t i ve h ea r t fa il u r e ( C H F ) r e qu i ri n g
p h a rm ac ol o gi c t r ea t me n t, a cu t e o r c h ro ni c m et a bo l ic ac id os is o r a h is t o r y o f l a ct ic ac id os is
s h ou l d b e e xc l u de d f r om t h e ra p y. Me t f o rm i n ca n a cc u mu la t e i n p at i en ts wh o se r en al f un ct i on is
i m pa i re d , t h us i nc r ea si ng t he r isk o f l ac ti c a ci dos is . It s u se is n o t r e co mm e nd e d i n p at i en ts
wi t h d ec r e as ed G F R s ( <6 0 m L /m in u te ) o r e le va t ed c re a ti n in e l e vel s ( ≥ 1 . 4 m g /d L fo r fe ma le s o r
≥ 1 . 5 m g /d L f o r m al es ) . Be c au se e ven a t em p o ra ry r e d uc t io n i n r e na l fu nc ti o n c ou ld ca us e
l a ct ic ac id os is in pa t ie n ts t ak in g m et f o rm in , th e m a nu f ac tu r e r re co mm end s wi t hh o ld i ng it af t e r
s om e ra d io lo g ic p r oc e dur e s (s ee D r ug In t e ra c ti ons ) . O th e r p r e di sp os in g fac t o rs fo r l a ct ic
a c id os is in cl u de th e f o ll owi n g : e xc e ss i ve a lc o ho l in g es t io n , C H F , s h ock , he p a ti c f ai l ur e ,
d e h yd ra t io n , s ep si s o r su r g e r y. Be ca us e a g in g i s a ss oc ia t e d wi t h r ed uc e d r e n al fu nc t io n ,
m e t fo rm i n sh o ul d b e t i t rat e d to th e m in im um ef f ect i ve do se an d re n al fu nc ti o n s ho ul d be
m o ni t o re d r e gu l ar l y. A c re a t in in e c le a r an ce ( C l C r ) t o en su r e a de q ua t e r e na l fu nc t io n s ho u ld be
m e as u re d i n p a ti en t s o ve r t he ag e o f 8 0 ye ar s , be c au se t he se pa t ie n ts a re mo r e s us ce p ti bl e to
d e ve l op in g l ac t ic ac id os is . 13 6
Drug Interactions

A l c oh ol po t en t ia t es th e ef f e ct of me t fo r mi n o n l act a t e m et a bo li sm . Pa t ie n ts sh ou l d b e
wa r n e d r eg a r di ng e xc e ssi ve a lc oh ol in t ak e wh i le ta k in g m et f o rm in .

C i me t i di n e in c re as e s p ea k m e tf o rm in pl a sm a co nc e nt r a ti o ns b y 6 0% , an d u s e o f a n
a l t er n a ti ve H 2 b lo ck e r o r a r ed uc t io n i n m et f o rm in d os e i s r e co mm en de d .

P a r e nt e r al c o nt r as t s t ud ie s (e . g. , p yel o gr a ph y o r a n gi o g ra p h y) t h at us e i od i na t ed
ma t e r i al s c a n re su l t i n ac u te r en a l f ai l ur e a n d met f o rm i n -i nd uc e d l ac ti c a ci d os is . Fo r
p a t ie n ts re q ui r in g s uc h a s t ud y, me t fo r mi n s ho ul d b e wi t hh e ld at t he ti me o f , or be f o re ,
a n d 4 8 h o ur s a f te r th e p ro c ed u re . Me t f o rm i n sh o ul d be r ei ns ti t u te d o nl y a ft e r r en al
f u nc t io n h as be e n r e - e val u a te d a n d d et e rm in e d t o b e n o rm a l.
Efficacy
A s mo no t he r a p y, m et f o rm i n ca n b e e xp e c t e d t o re d uc e t h e A 1 C b y 1 . 5% to 1 .7 % a n d t he F P G
b y 5 0 to 70 m g /d L . I n p at i e nt s wh o h a ve d e ve lo pe d s ec o nd a r y fa i lu r e t o su l f on yl u re as , th e
a d di t io n o f m e t fo rm i n can b e e xp e c t ed to p ro du ce a s im il a r o r s li g ht l y g rea t e r i mp r o vem e nt in
t h e FP G a nd A 1 C .1 34
Dosage and Clinical Use
Me t f o r m i n is ad mi n is te r ed wi t h me al s t o m in im i ze i t s G I s i de ef f ec ts . Th ese d is tu r b an ce s a ls o
c a n b e mi n im i zed b y s l owl y i n c r e as in g t h e d os e (e . g . , 5 00 m g o nc e o r t wic e d a il y i ni t ia ll y,
f o l lo we d b y we e kl y o r biwe e k l y i nc r em en t s o f 5 00 mg da i l y) . Me t f o r mi n i s d os e d t wo t o th r ee
t i me s d ai l y ( 50 0 t o 1 , 00 0 m g p e r d os e ; ma xi m u m d o se is 2 , 55 0 m g d ai l y or 8 5 0 mg P O TI D ) ,
u n le ss an e xt e n de d - re l ea s e p r ep a ra t io n i s p r esc ri b ed . C li ni ci a ns s h ou ld ob t a in a S r C r an d
h e p at ic fu nc t io n te st s a t b a se li n e a nd t he n a nn u al l y. M e t f o r mi n s ho ul d n o t b e u se d i n p a ti e nt s
o l de r t ha n 8 0 yea r s u nl es s a C l C r de mo ns t r at es no r m al re n al fu nc t io n . Pa ti e n ts a r e c an d id a te s
f o r t re a tm en t i f th e Cl C r is > 60 m L /m in u te .
B e c au se m e t fo r mi n a nd th e s u lf o n ylu r ea s a r e e qua l l y ef f ec t i ve i n r ed uc i ng F P G c on ce n tr a ti o ns ,
e i t he r c a n b e us e d as in it i a l t he r ap y. R e la t i ve t o th e s u lf o n ylu r ea s , me t f orm i n h as
P . 5 0 -5 3
t h e a d va nt a ge o f d ec re as i ng he p at ic gl uc os e o u tp u t , i mp r o vin g i ns u li n r es is t an ce , r ed uc in g
p l as ma in su li n c o nc en t r at i o ns , a nd im p ro vi n g t he l i pi d p r o fi le . It ma y p r odu c e so m e we i g h t l oss
( o r a t l ea st no we i g ht ga in ) a nd ra r e l y c au se s h ypo g l yce mi a wh e n us e d a lo n e . Th u s , i t is
p r e f er r e d as mo no t he r a py i n ob es e p a ti e nt s (a ls o s ee Q u es ti o ns 52 , 5 3 , 54 a nd 58 , 5 9 , 6 0 ) .
Nonsulfonylurea Insulin Secretagogues
R e p a gl in i de ( P ra n di n i n th e U ni t ed S ta t es ; No vo N o r m i n o t he r c o un t ri e s) an d na t eg li n id e
( S t a r li x) a r e n on su l fo n ylu r e a i ns ul i n se c re t ag o gue s (i . e. , s t im ul a te in su l in s ec r e ti on ) ; th e y
b e lo n g t o a c l ass o f a gen t s r e fe r r e d t o as me gl i tin i de s a n d am i no ac id der i va t i ves ,
r e s pe ct i ve l y. Re p ag li n ide wa s a pp r o ved b y th e FD A i n De c em be r 1 9 97 and n at e gl in i de wa s
a p p ro ve d i n D ec em be r 20 0 0 1 3 9 , 14 0 , 1 41 ( se e Ta ble 5 0 -2 9 ).
Mechanism of Action
L i ke th e s ul f on yl u r ea s, th e se ag e nt s c lo se th e ad e n os in e t r ip h os ph a te (A TP ) - s e n si ti ve
p o t ass i um c h an ne ls in t he β - ce l l, wh i ch le a ds to c e ll m em b r an e d ep o la r i za t i on , a n i n fl u x o f
C a 2 + , an d s ec r et i on of ins u li n . U n li ke th e s ul f on ylu r e as , t h e y ha ve a r a pi d o n se t a n d s ho r te r
d u r a ti on o f ac t io n s o t h at t h e y a r e g i ve n wi t h m ea l s t o e nh a nc e p os t pr a nd i al gl uc os e
u t i li za t io n .
Pharmacokinetics
R e p a gl in i de ha s a b i oa va i la b il i t y o f 56 % a nd is ra p id l y ab s or b ed an d e xc r e t e d. 1 42 It s C m a x
o cc u rs a t a pp r o xi m a te l y 1 h ou r an d i ts ha l f -l i fe i s 1 ho u r . I t i s c om pl e te l y m e ta b ol i ze d ( C YP
3 A 4 ) b y t h e l i ve r t o i na cti ve p r od uc ts ; 90 % i s e xc r e t e d i n t he fe ce s a n d 8% is e xc r e t ed i n
u r i ne . It is hi gh l y ( >9 8 % ) p r o te i n b ou nd ( vo lu me of d is t ri b ut i on [ Vd ] , 3 1 L ) .
N a t e gl i ni de ha s a bi oa vai l ab i li t y of 7 3% an d i s r ap i dl y a bs o rb e d wi t h a C m a x o c c ur r i ng wi t h in 1
h o u r a f te r do si ng ; it s h alf - l i fe is 1 . 5 h ou r s. N a te g li n id e i s m et a bo li ze d ( C YP 2 C 9 , 7 0 % a nd
C YP 3 A 4 , 3 0 %) t o l ess po t e nt co mp o un ds , wi t h 75 % be in g e xc r e t e d i n t h e u r in e an d 1 0% in t he
f e ce s ; 1 6% of na t eg l in ide is e xc r e t ed un ch an g ed i n t h e u r in e . I t i s h ig hl y ( 9 8 % ) p r ot e in bo un d ,
p r i ma r il y t o a lb um i n a nd , t o a le ss e r e xt e n t , to α 1 a c id gl yc op r o te in .
Ad verse Effects
Mi l d h yp o gl yc em i a ma y o cc u r , p a rt ic u la r l y i f in ges t io n i s n o t f ol lo we d b y fo o d i n a n i nd i vi du a l
wh o s e bl o od gl uc os e c on c en t r at i on s a r e wi t h i n th e no r ma l r a ng e . A we i gh t ga i n o f 0 . 9 t o 3 k g
c om p a re d wi t h b as el i ne h a s b ee n o bs e r ve d.
Contraindications and Precautions
B e c au se a f un c ti on i ng pa n c re as is re q ui r ed , th ese a ge n ts s h ou ld no t be us e d i n p eo p le wi t h
t yp e 1 d ia b et es . Th es e ag e n ts s h ou ld be ca u ti ou sl y u se d i n p a ti e nt s wi t h l ive r d ys f un ct i on .
N a t e gl i ni de ' s c le a r an ce is no t af f ec t ed in pa ti e n ts wi t h m od e ra t e -s e ve re r en a l i ns u ff ic i e n c y,
wh e r e a s t h e cl e a ra nc e of r e pa g li ni d e is r ed uc e d in p at i en ts wi t h s e ve r e r en a l i ns u ff ic i en c y.
N e ve r t h el es s, i t ma y b e u s ed s a f el y. 1 43
Drug Interactions
W hen e va lu a te d i n c li ni ca l s t ud i es , r e pa g li ni d e d id n ot in t e ra ct wi t h di g o xi n , t he op h yl li ne , o r
wa r f a r i n . F u r th e rm o re , c im e ti d in e d id no t af f ec t i ts me t ab ol is m . D r u gs th a t i n du ce th e P4 5 0
s ys t em (e . g. , ri f am pi n ) co u ld t he o re t ic al l y de c re as e re p ag li n id e ' s e ff ec t s. C o n ve r se l y, d r u gs
t h a t i nh i bi t t h e P 4 50 s ys te m (e . g. , a zol e a n ti f un gal a ge n ts a n d ma c ro l id es ) c ou l d e nh a nc e i ts
e f f ec ts . Th e l a tt e r c on cep t w a s es ta b li sh e d wh e n 3 da ys of t re a tm en t wi t h g em f ib r o zil o r
i t r ac o na zo le in c re as e d re p a gl in i de ' s p la sm a c onc e nt r a ti o n - t im e c u r ve ( AU C ) b y 2 8 .6 - f ol d a nd
8 . 1 fo ld , re sp e ct i vel y. Th e co mb i na t io n i nc r ea s ed t h e A U C b y 70 . 4 f o ld . 144 N e w d r u g
i n t er a ct i on wa r n in gs ha ve b ee n i nc l ud ed in t he pa ck a ge in se r ts f or L op id , S p o ro n a x, a n d
P r a n di n . B ec a us e h yp og lyc e mi a h a s b ee n r e po r t ed i n p at i en ts t ak in g t h e
g e mf i b ro zi l/ r e pa gl i ni d e co m bi n at io n , t h ei r u s e t oge t h e r is c o ns id e r ed c o nt ra i nd ic a te d .
N a t e gl i ni de is a p ot e nt i al i n hi bi t o r o f C YP 2 C 9 . W h e n e va l ua t ed in c l in ic al s t ud i es , t h er e we r e
n o c l in ic al l y r el e va nt in te r a ct i on s wi t h na t eg l in ide a nd gl yb u ri d e, me t fo r mi n , d i go xi n ,
d i cl o fe na c , o r wa r f a ri n .
Efficacy
Th e e f fi c ac y o f r ep a gl in id e is c om pa r a bl e t o m e tfo r m in an d t h e su l fo n yl ure a s. 1 41 W he n u se d
a s m on o th e r ap y, t he m ea n de c re as e i n F P G , po st p r a nd ia l g l uc os e, an d the A 1 C val u es we r e 61
m g /d L , 1 04 mg / dL , a n d 1. 7 % , r es p ec ti ve l y, c om pa r e d wi t h p la ce b o ( - 31 . 0 m g /d L , - 4 7. 6 m g /d L ,
a n d -0 . 6 % c om pa r e d wi t h b as el in e ) . Ne wl y d i a gno s ed pa t ie n ts wh o ha ve n e ve r be en t r ea t ed
wi t h o r a l a ge n ts a n d t hos e wh o se A 1 C is < 8% re sp o n d mo r e p r o fo un d l y tha n po o rl y c on t r ol le d
i n di vi d ua ls al r ea d y o n t re a tm e nt . W he n r ep a gl i nid e wa s ad de d to m e t fo rm i n, t he m e an de cl in e
i n F P G wa s a pp r o xi m a te ly 4 0 mg / dL an d t h e me an d ec r ea se in A 1 C wa s 1 .4 % f ro m b as el i ne
va l u es .
N a t e gl i ni de as m o no t he ra p y r es u lt s i n a m e an dec r e as e i n F P G an d A 1 C by 1 3 . 6 m g/ d L a nd
0 . 7 %, r es pe c ti ve l y, c omp a r ed wi t h pl ac e bo ( -4 . 5 m g /d L a n d 0 .5 % c om p are d wi t h b a se li n e) .
Dosage and Clinical Use
R e p a gl in i de an d n a te g li ni d e a r e a pp r o ve d t o t r ea t p e op le wi t h t ype 2 d ia be t es as m o no t he r ap y
o r in co mb i na t io n wi t h me t f o rm in ; re p ag li n id e i s al s o a pp r o ved f o r us e wi th t hi a zo li di n ed i on es
( TZ D s ) . 1 41 B ec au se t hey h a ve t he s am e m ec h ani sm o f ac t io n a s t h e su l fo n yl u re as , c om b in in g
t h es e a g en t s d oe s n ot p ro d uc e a n y ad d it i on al ben e f it . W hen r ep a gl in i de is us ed as th e i n it i al
t r e a tm en t i n p a ti e nt s who a r e “ na i ve ” t o or a l a nt id i ab e ti c t h e ra p y or in pat i e nt s wi t h A 1 C val u es
< 8 % , t he r ec om me n de d s t a rt i ng do se is 0. 5 m g wi t h e ac h m e al . W hen use d in pa t ie n ts wh o
h a ve fa i le d s ul f on yl u re as o r in th os e wi t h A 1 C va lu e s > 8% , th e i ni t ia l d os e i s 1 to 2 mg wi t h
e a ch m e al . D os es c an b e t it r a te d we e kl y a t a ra te o f 1 m g /m ea l t o a ma xi m um o f 4 m g/ d os e o r
1 6 m g /d a y. Th e re co mme n d ed s t a rt i ng do se of na t e gl in i de is 1 2 0 mg TI D b e fo r e m ea ls ; fo r
p a t ie n ts c lo se t o t he i r A 1 C g o al , a do se o f 6 0 mg TI D m a y b e u se d . D o se s s ho u ld be ta ke n 0 t o
3 0 m i nu t es b e fo r e th e me a l , om i tt e d i f a m e al is s ki p pe d a n d a dd e d i f a n e xt r a m e al is i n ge st e d
( r e p ag li n id e o n l y) . R e pag l in i de s h ou l d b e i ni ti a ted a t a 0. 5 m g d os e i n p at i e nt s wi t h se ve r e
r e n al d ysf u nc ti o n a nd s ho u ld be t it r a te d c au t io us ly i n pa t ie n ts wi t h l i ve r dys f u nc t io n .
Sulfonylureas
U n t i l me t f or mi n a n d o th er a n ti di a be t ic s b ec am e ava i l ab l e i n t he U ni t e d S ta t es , s u lf o n ylu r ea s
we r e t h e fi rs t - li ne p ha rma c ol o gi c t r ea tm e nt f or peo p le wi t h t ype 2 d ia b et es wh o h ad fa il e d
P . 5 0 -5 4
d i e t a nd e xe r c is e t he r a py. S e ve n di f fe r en t s u lf o nyl u r e as ar e a vai la b le in th e U ni t ed S ta t es . The
f o u r f i rs t - ge ne r a ti o n su l fo n yl u re as ( ac e to he xa m i de [ D ym el o r ], c h lo r p ro p am i de [ Di a bi n es e] ,
t o l a zam id e [ To l i na se ] , an d to l bu t am id e [ O r i na se ]) a r e c on si d er e d e qu a ll y e f f ec t i ve d es pi t e
d i f fe r e nc es i n t h ei r ph a rm ac o ki ne t ic p r o pe r t ie s an d ad ve r se ef f ec t p r o fi les (s e e t h e f ol lo wi n g
d i sc us si on an d Ta bl e 5 0 - 2 9 ) .
G l i p i zid e ( Gl uc o t ro l ) a nd g l yb u ri de ( D ia B e ta , Mi c ro n as e ) , t wo s ec on d -g e ne r a ti o n s ul f on yl u re as ,
we r e f i r st in t r od uc e d i nt o t h e Un i te d St a te s i n Ma y 1 9 8 4. G l im ep i ri d e ( A ma r yl ) wa s ap p ro ve d
f o r us e i n 1 99 5 . Th e s e ag e n ts a r e a p p ro xi m a t el y 1 0 0 t im es mo r e p o te n t t ha n th e fi rs t g e n er a ti o n su l fo n yl u re as o n a mi ll i gr am - f o r -mi l li gr a m b as is ; ho we ve r , t he re is no e vid e nc e t h at
t h e y a re mo r e e f fe ct i ve cl i ni ca l l y. Th e y h a ve a r ela t i ve l y fa vo r ab l e si d e - e f fe c t p r of i le an d h a ve
a d u ra t io n o f a ct i vi t y th at r e qu i re s n o m o re th a n o n e o r t wo da i l y d os es . Th e b as is on wh i c h
s p ec if ic ag e nt s a r e s el ect e d fo r p a ti e nt s i s d isc uss e d i n ca s e st u di es th a t f o l lo w t h is
i n t ro d uc t io n .
Mechanism of Action
Pancreatic Effects
S u l f on yl u re as st im u la t e th e r el ea se o f i ns ul in f rom pa nc r e at ic β - ce ll s a nd e n ha nc e β -c el l
s e ns it i vi t y to gl uc os e . A s p ec if ic su l fo n ylu r e a r ece p t o r t ha t i s l in ke d c lo s el y t o th e A TP s e ns it i ve p o ta ss i um i o n c h an n el ha s b ee n i de n ti fi e d o n t h e β - ce l l, an d s ulf o n yl u re as a re
b e li e ve d t o i nh i bi t th is po t as si um io n c h an ne l . As a r e su lt , th e y bl oc k t h e e f fl u x o f p ot a ss iu m
a n d l o we r t he m em b r an e p o te n ti a l ca us i ng de p ola r i za ti o n . Th e vo lt a ge - dep e n d e n t ca lc i um
c h an n el s t he n o p en , i nc re a si n g in t r ac el l ul a r c al ciu m c on c en t ra t io n . Th e i nc r e as ed in t r ac el lu l ar
c o nc en t r at i on of ca lc iu m u l ti ma t el y s ti mu la t es in su l in se c re t io n . 4 7 , 1 4 5 I nsu l in le ve ls t en d t o
r e t u rn t o b as el in e val u es a f t er a f e w m on t hs of con t i nu ed su l fo n yl ur e a us e.
Extrapancreatic Effects
S u l f on yl u re as ca n n o rm al i ze he pa t ic gl uc os e p r odu c ti o n a nd pa r t ia ll y r e ve rs e i ns u li n re si st a nc e
i n th e p e ri p he r al t iss u es o f pe o pl e wi t h t yp e 2 di ab e t es . W het h er t he se “ ext r a p a n c r ea t ic ”
e f f ec ts o f t he s u lf o n ylu r ea s a r e d i re c t e f fe ct s o f th e se ag e nt s o r a r e s ec on d a r y to im p ro ve d
i n su li n re l ea se an d l o we r g l uc os e c on ce n tr a ti o ns r e m ai ns to be es t ab li sh ed . I n a n y c as e , i t is
c l ea r th a t t is su es be co me mo r e re sp o ns i ve t o l owe r c o nc e nt r a ti o ns o f end o g en ou s i ns ul i n i n
t yp e 2 p a ti en t s t r ea t ed wi t h s ul f on yl u r ea s. 1 46
Pharmacokinetics
Th e b i op ha r ma ce u ti ca l an d ph a rm ac ok i ne ti c p a ram e te r s o f t h e su l fo n yl u rea s a r e s um ma r i zed
i n th e f o ll o wi n g t e xt a n d i n Ta b le 50 - 29 . 14 6 , 1 4 7 Th e du r a ti on o f h yp og l ycem ic ac t i vit y is
r e l at e d t o t h e h al f - li fe o f t h es e c om po u nd s o nl y in ve r y g en e r al te r ms a n d m a y c o r re l at e p o o rl y
i n s om e c as es . Al l s ul f onyl u r e as ar e hi gh l y p ro t ein b ou n d ( 90 % to 10 0% ) , m a in l y to al b um in ;
h o we ve r , b in di n g c ha r act e r is t ics va r y am o ng in divi d u al su l fo n yl ur e as . F oo d do es no t i mp a i r t he
e xt e n t o f d r u g a bs or p ti on b ut ma y d el a y th e ti me t o pe ak le ve ls of so me a g e nt s.
Th e r e la t io n b e t we e n s ulf o n yl u re a d os es an d t h eir b lo o d g lu co se – lo we r i n g e f f ec t r e qu i re s
f u r t he r s t ud y. O n e l on g - te r m s tu d y co mp a ri n g g l yb u r id e a n d g li pi zi d e sh owe d l i t tl e o r no
i m p ro ve me n t i n g lu co se c o nt r o l a t d os ag es ≥ 1 0 m g /d a y o f e it h er a ge n t. 14 8 In si ng l e -d os e a nd
s h o rt - t e rm s tu d ie s wi t h gl i pi zi d e, an in c re as e d b lo o d g lu c os e – lo we r i n g e f fe c t wa s n ot e d wi t h up
t o 10 mg da il y o f g li p i zide . 1 49 , 15 0 I n a pl a ce bo - co n t r ol le d , d ou b le - bl i nd s tu d y e xa m i ni n g t he
e f f ec t o f g l ip i zid e 10 , 2 0 , o r 40 m g /d a y in p at ie n ts wi t h t yp e 2 di a be t es , t he ma xi m a l i ns u li n
r e s po ns e a n d b lo od gl uco s e – l o we r in g e f f ec t wa s a c hi e ve d wi t h a g li p i zid e d os e o f 10
m g /d a y. 15 0 Th es e d a ta s u gg es t th a t su l fo n yl u rea s o p e ra t e wi t h i n a n a r row r a n g e of pl as ma
c o nc en t r at i on s t ha t m a y b e ac hi e ve d wi t h lo w d os a ge s o f t h e d r ug . Th e ref o r e , t he r e i s a ne ed
t o r e -e va lu a te ma xi m u m r e c omm e nd e d d ai l y do ses o f 4 0 mg f or gl i pi zi de an d 20 m g fo r
g l yb u ri d e. F ur t he r mo r e , a d di t io n o f a se co n d o r al a g en t o r in su l in m a y be i n di ca t ed f o r p at i en ts
n o lo ng e r re sp o nd in g to d o se s o f g l yb ur i de o r g lip i zi de ≥ 1 0 mg .
B e c au se of i ts va ri a bl e re n al e xc r e t io n , l on g s e rum ha l f - l if e , l on g d u ra t ion o f h yp og l yc em ic
a c ti vi t y, an d a d ve rs e e f fe c ts , c hl o r pr o pa mi d e h as f al le n i n to di su se an d s h ou l d b e a vo id ed in
t h e e l de r l y or in pa t ie n ts wi t h r e na l i mp a ir me n t ( se e Q u es ti o n 7 0 ) .
G l i p i zid e i s a n i nt e rm e dia t e - ac ti n g se co n d -g en e ra t i on ag e nt wi t h a ha l f -l i fe o f 2 to 4 h ou r s, bu t
a d u ra t io n o f a ct i on of 12 t o 2 4 h ou r s . Ma n y p a t ie n ts , es pe ci al l y t ho se r ec e i vin g sm a ll to
i n t er m ed ia t e d ai l y do se s o f th is d ru g ( < 20 mg ) , re q ui r e o n l y o n e d os e p e r d a y. G li p i zid e i s
e xt e n s i ve l y m e ta b ol i zed b y t h e l i ve r t o i na c ti ve p ro d uc ts t ha t a r e e li mi n at ed p ri m ar i l y b y t h e
k i dn e y. 14 6 , 1 4 7 F oo d d e la ys t he r at e o f a bs o r pt i on o f g li p i zid e b u t n ot it s b i oa va i la b il it y. 1 5 1
A d m in is t ra t io n 3 0 m in u tes be f o re me al s h as be en s ug g es t ed , b u t t hi s h as b e e n di s pu t ed b y
o n e s tu d y, wh i ch no t ed no ac u te e ff ec t s o f t hi s d ru g in pa t ie n ts wh o ha d be e n t ak i ng it
c h r on ic al l y wi t h m e al s. 15 1 A s us t ai ne d - re l ea se fo r m ul a ti on o f gl i pi zi d e, G l u c ot r ol XL , al so is
a va i la b le .
G l yb u r i de ( or gl i be nc l ami d e ) is a l on g e r -a ct i ng s ec o nd - ge n e ra t io n a g en t s im i la r to gl ip i zi de .
Th e h a lf - li f e i s a pp r o xi ma t e l y 1 . 5 t o 4 ho u rs fo l lowi n g s in g le - do se st u di es a n d u p t o 1 3 .7 ho u rs
wh e n c h ro n ic al l y ad mi nis t e re d . 1 5 2 N e ve r th e le ss, a s wi t h gl i pi zi de , th e du r a ti o n o f a ct i on c a n
l a st f or up t o 2 4 h ou r s i n m an y p a ti en t s, al l o wi ng s i ng le da i l y d o si ng wi t h s ma l l t o i nt e rm e di a te
d o se s ( < 15 mg ) . Gl yb u r id e is m e ta bo l i zed c o mp le t e l y b y t h e l i ver t o ac t i ve m e t ab o li t es , h al f of
wh i c h a re e xc r e te d i n the u ri n e a nd t he re ma i nde r el im i na t ed vi a t he bi l ia r y t r ac t . 15 3 Un li ke
g l ip i zi de , fo od do e s n ot d e la y t h e r a te o r e xt e n t o f ab so r p ti o n o f g l ybu r ide , an d th e t im e o f
i n ge s ti on r el a ti ve t o me al s a p pe a rs to be un im p o rt a n t i n p a ti en t s o n ch r o nic t he r ap y. 1 54 Th e
m ic r o ni ze d g l ybu r i de ta bl e ts ( 3 mg ) a re no t b i oe qu i va le n t t o th os e o f t h e co n ve n ti o na ll y
f o r mu l at e d 5 -m g t a bl e ts . Th u s , p a ti e nt s s wi t ch e d f r o m t he co n ve nt i on al f orm t o t he m ic r o ni ze d
p r o du c t mu s t b e r e ti t ra t ed .
G l i me p i ri de is a l on g -a cti n g s ec on d -g e ne r a ti o n su l f on yl u re a . Th e h al f -l i fe o f gl im ep i ri d e is 9
h o u rs , a n d i ts du r at i on of a ct i on i s 2 4 h o ur s ; t hu s, i t c an be gi ve n o nc e d ai l y. Th e a b so r pt i on
o f gl im e pi r id e i s u na f fe c te d b y fo od , an d i ts pe ak e f f ec t o n p l asm a g l uc os e c on ce n t ra t io ns is
o b se r ve d 2 to 3 h ou r s a ft e r ea ch do se . G li me p ir id e is c om pl e te l y me t ab oli ze d b y th e l i ve r, an d
i t s p r in ci p al m e ta b ol it e ha s 3 0 % o f t h e ac t i vit y o f t h e p a r en t d r ug . Me t a b oli t es a re e xc r e te d i n
f e ce s a n d u ri n e. G l im ep ir i d e is t he fi r st su l fo n ylur e a ap p ro ve d b y t h e F D A f o r c on c ur r e nt us e
wi t h i ns u li n ; h o we ve r , a ny s u l fo n y lu r e a ca n b e u se d in c om b in a ti o n t he r apy. 1 5 5 , 15 6 , 1 57
Ad verse Effects
Th e p r im a r y s i de ef f ec ts o f t he s u lf o n ylu r ea s a r e h yp o g l yc em i a ( p ar t ic ul a rl y f o r th os e t h at a re
l o ng - ac t in g ) a n d
P . 5 0 -5 5
we i g h t ga i n ( se e Q ue st i on s 6 9 a n d 7 4 ). O t he r ad ve r s e e ff e ct s a t tr i bu t ed t o t h e s ul f on yl u re as
g e n er a ll y a r e so in f r eq uen t an d m il d t h a t < 2% of p a t ie n ts d is co n ti n ue th es e a g en t s b ec au se of
t h em . In ge n er a l, t he t ype , in ci d en ce , a n d s e ver i ty o f r ep o r te d s id e e f f ec ts a re sim i la r fo r al l
t h e s ul f on yl u r ea s. A n imp o r t an t e xc e p t io n i s c hl or p r o pa mi d e, wh i ch ha s se ve r a l u ni q ue ad ve r se
e f f ec ts (s e e f ol l o wi n g d isc us si o n ). A d ve rs e r e ac tio n s t o t h e su l fo n yl u re as i n cl ud e G I s ym pt om s
( n a us ea , fu l ln es s, bl o at in g th a t c an be r el ie ve d i f t a ke n wi t h me a ls ) , r a r e b l oo d d ys c ra si as ,
a l le r g ic d e rm a to lo g ic re ac t io ns , he pa t o to xi c i t y, an d h ypo t h yr oi di s m 1 58 (al s o se e Q ue s ti on s 6 7 ,
6 8 , 6 9 , 7 0 a nd 76 ) .
A d is u lf i ra m ( A n ta b us e -l ik e ) re ac t io n o cc u rs wh en p at i en ts t ak e ce r t ai n or a l s ul f o n ylu r ea d ru gs
a n d d r in k e t ha no l . I t i s mo s t f r eq u en t l y ass oc i at ed wi t h ch lo r p r op am id e , oc cu r r in g i n
a p p ro xi m a t el y o ne - t hi r d o f al l p a ti e nt s r ec e i vin g it . Th e fl us h in g re ac t io n se e n s o o f te n wi t h
c h lo r p ro p am id e i s r a re wi t h o t he r s u lf o n ylu r ea s . 15 8
Syndrome of Inappropriate Antidiuretic Hormone Secretion
C h l o rp r o pa mi de , an d t o a mu ch le ss e r e xt e n t , to lb u t am id e , ma y e n ha nc e t h e re l ea se of
a n t id iu r e ti c h o rm on e ( A DH ) c en t r al l y, e n ha nc e the e f fe ct of A D H on t he k id n e y, a n d o ve r r id e
t h e i n hi bi t o r y ef f ec ts of wa t e r l o ad i ng on A D H re le a se , re su l ti n g i n s ynd r om e o f in ap p r op r ia t e
a n t id iu r e ti c h o rm on e s ecr e t io n . 14 6 Thi s a n ti di u r et i c e f fe ct ha s b e en us ed c l in ic al l y t o t r ea t
d i ab e te s i ns i pi du s . 1 59 In t he U K P D S , t h e i nc r eas e i n b l oo d p r es su r e s een i n p at i en ts on
c h lo r p ro p am id e wa s l ik ely d u e to wa t e r re t en t io n . 2 2 In co n tr a st to ch lo r p ro p am i de an d
t o l bu t am id e , g li pi zi d e, glyb u r i de , to l a zam id e , a nd a ce t oh e xa m i de ha ve a m i ld di u re t ic e f f ec t .
Contraindications and Precautions
C o n t r ai nd ic a ti o ns to th e u s e o f s ul f on yl u re as in clu d e t h e f ol l o wi n g:

Typ e 1 d ia b et es

P r e g na nc y o r br e as t -f e ed i ng , be ca us e t h es e a gen t s ( e xc e p t g l yb ur i de ) c an c ro ss th e
p l ac e nt al b ar r i er an d c an b e e xc r e t e d i n to br e as t m i lk

D o c um en t ed h yp er se n si ti vi t y t o s ul f on yl u re a s

S e ve r e he pa t ic or r en a l d ys f un c ti o n

S e ve r e , a cu t e i nt e rc u r ren t il l ne ss (e . g. , in f ec ti o n, MI ) , s u r ge r y, o r o th e r st r e ss th a t ca n
u n d ul y a ff ec t bl oo d g l uco s e co n t ro l
Drug Interactions
D r u g in t er a ct i on s wi t h sul f o n ylu r ea s h a ve a ph a rm ac o d yna mi c o r p h a rm ac ok i ne t ic b a si s.
P h a r ma co d yna mi c i n te r ac t io ns oc cu r wi t h d r u gs th a t a l te r gl uc os e t o le r anc e i n t ri ns ic a ll y
t h r o ug h t h ei r e f f ec ts on in s ul in se c re t io n , g lu co se p r o du ct i on , a n d p e ri ph er a l g l uc os e
u t i li za t io n . Th e se a re di sc us s ed l a t er in t hi s ch a pt e r in s ec t io ns a dd r es si ng d r ug - in d uc ed
h yp o g l yc em i a a nd h ype rg l yc em ia . Ph a rm ac ok i ne ti c i n te r ac t io ns oc cu r wh en d r ug s a lt e r t h e
a b so r p ti on , m e ta b ol is m, e l im in a ti o n, o r p r ot e in bin d in g o f th e s ul f on yl u r eas .
Mo s t o f th e re p o rt e d p har m ac ok i ne t ic d r u g i nt e rac t io ns wi t h th e s ul f on yl u re a s i n vol ve
c h lo r p ro p am id e a nd t ol bu t am i de , b ec a us e t h es e a r e th e o l de st ag e nt s a nd we r e o nc e t he mo st
c om mo n l y p r es c ri b ed and s tu di e d. H o we ve r , be ca u se m o st of t he c l in ic al ly s i gn i fi ca n t
i n t er a ct i on s oc cu r wi t h dr u g s t ha t a l te r li ve r m e tab o li sm o r u ri n a r y e xc r e t io n , p os si b le
i n t er a ct i on s wi t h al l o f the su l fo n yl u re as m us t be a n t ic ip a te d e ve n t h ou g h t h e o u tc om es m a y b e
q u i te di f fe r e nt . Fo r e xa m p l e , a d r u g t ha t i n hi bi t s th e he p a t ic m e ta b ol is m of t ol b ut a mi de ca n
i n c re as e i ts h ypo g l yc e mic ac t i vit y; co n ve rs e l y, t he sa me d ru g a c tu al l y may d i mi n is h t he
h yp o g l yc em ic ac t i vit y o f a c et o he xa m i d e b y in h ib i ti n g f o rm a ti o n o f i ts ac ti ve me t ab o li t e. Th is
h yp o t he si s h as no t b e en t e st e d.
Th e s ec o n d - ge n er a ti o n su l f on yl u re as ( gl i pi zi de , gl yb u r id e , a nd gl im e pi r id e) a r e d os e d in
m i ll ig r am r at h er t ha n g r am qu a nt i ti es an d th us s ee m to be le ss l ik e l y t o i nt e r ac t wi t h o t he r
d r u gs on a p ha r ma co ki ne t ic ba si s . G l ip i zi de an d g l yb u ri d e a ls o d if f e r f r om t he fi r st - ge n e ra t io n
a g e nt s i n t ha t th e y a re hi g hl y b ou n d t o a l bu mi n at n on i on ic r at h er t ha n i on i c si t es . 14 6 , 1 4 7 O n
t h is ba si s , t he se ag e nt s a r e un li ke l y t o i nt e ra c t wi t h o t he r hi g hl y p ro t ei n - bo u n d d ru gs , s uc h a s
p h e n ylb u ta zo ne , s a li c ylat e s , o r c e rt a in s u lf o na mid e an t ib io t ic s t ha t ha ve b e e n r ep o r te d t o
e n h an ce th e e f f ec ts o f the f i rs t -g e ne r at i on su lf o nyl u r e as . Ho we ve r , t h es e h i gh l y p ro t ei n - bo un d
d r u gs ap pe a r to i n t er ac t wi t h t h e s ul f on yl u re as b y a l te r in g th ei r he p at ic me t a bo li sm as we l l.
Th e r e f o re , gl ip i zi de an d g l yb u ri d e sh o ul d b e u sed ca u ti o us l y wi t h d r ug s re p o r te d t o i n te r ac t
wi t h f i rs t - ge n e ra ti o n s ul fo n yl u re as . Th e m an y p o te n t ia l p ha r ma co ki n et ic int e r ac t io ns r ep o r te d
wi t h t h e s ul f on yl u re as have b e en r e vie we d e xt e n si ve l y, an d o n l y th e m o re i m po r t an t o r
c l in ic al l y si gn i fi ca n t i n te ra c ti o ns a r e i nc l ud ed in Ta b le 50 - 3 1.
Efficacy
L i ke m e t fo rm i n, t he s u lf on yl u r ea s d ec r ea se t he A 1 C b y 1 .5 % t o 1 . 7% an d th e F P G b y 5 0% t o
7 0 % . I n p a ti en t s wh o h ave d e ve lo p ed s ec o nd a r y f a i lu r e t o m a xi m um d o ses o f me t fo r mi n , t h e
a d di t io n o f s u lf o n ylu r ea s wi l l p ro d uc e s im il a r im pr o ve m en ts in t he A 1 C a nd F P G , u n le ss th e
d i se as e h as p ro g re ss e d a n d t h e p an c re as is n o lo n g er ab l e t o r es p on d ap p r op r i at el y. 4 7
Dosage and Clinical Use
A s mo no t he r a p y, t h e su l fo n yl u re as a re ve r y e ff ec ti ve a nd r el a ti ve l y s a fe ; th e y a r e a ls o
r e l at i ve l y i n e xp e ns i ve a nd e as y t o t it r a te . N e ve rt he l es s, so me c l in ic ia n s f avo r u se o f me t fo r mi n
f o r in i ti al t he r ap y si n ce it d oe s n o t ca us e we i gh t g a in o r h yp og l yc emi a . Th e c h oi ce of ag e n ts i s
d i sc us se d m or e fu ll y i n th e c as e s t ud i es t h at f ol lo w t h i s s ec ti o n. Th e do se s o f th e
s u lf o n ylu r ea s a r e d is pl a ye d in Ta b le 50 - 29 . As a g e n er a l r ul e , o n e sh o ul d b e gi n wi t h l o w d os es
a n d t i t ra t e u p wa r d e ve r y 1 t o 2 we e ks u n ti l th e d es i r ed go al is ac hi e ved . Exc e e d i n g ma xi m u m
d o se s is n ot li ke l y to p rod u ce im p ro ve me n t, bu t m a y pu t th e p a ti e nt a t r is k f o r a d ve rs e e f fe c ts
( s e e Q u es t io ns 55 , 5 6 , 57 , 58 , 59 , 6 0 a n d 7 4 ).
Thiazolidinediones
R o s ig l it a zo ne ( A van d ia , G l a xo S m i t h Kl i ne ) a n d p io g li t a zon e ( Ac t os , Ta k e da P h ar m ac eu t ic al s)
we r e a p p ro ve d i n 1 9 99 an d a re th e t wo a va i la b le TZ D s i n t h e U n i te d S t a tes . Tr o gl i ta zo n e
( R e zu l in ) wa s F D A a pp r ove d i n 1 99 7 , b ut wi t h d rawn f r o m th e m a rk et in Ma r c h 2 00 0 b ec a us e o f
h e p at o xi c i t y.
Mechanism of Action
Th e TZ D s a r e o f te n r e fe rr e d to as i ns u li n s en si t i ze r s , b ut t he fu l l n at u re o f t h ei r ef f ec ts
r e m ai ns in co mp le t el y u nd e r st o od . Cl i ni ca ll y, t he se d r ug s d ec r ea se in su li n r e si st a nc e i n m usc l e
P . 5 0 -5 6
a n d l i ve r , wh i c h e nh a nc es gl uc os e ut il i za ti o n a nd d e c re as es he p at ic gl uc os e o u tp u t . Th e
a m el io r a ti o n o f i ns ul i n r es is t an ce r ed uc e s in s ul in , g l uc os e, an d f re e f a tt y a c id le ve ls , a n d h as
p o si t i ve e f fe ct s o n l ip i d le ve l s. ( S ee E f fi ca c y b e low. ) B e c a us e TZ D s e nh anc e th e e f fe c t o f
i n su li n , e nd o ge n ou s i ns ul i n m us t b e p r es en t fo r th e m t o e xe r t t h ei r be ne f ic i al ef f ec ts on
g l yc em ia . Th e p r ec is e mo l ec ul a r a c ti on s o f t h es e a g en ts r em ai n t o be c l ari f i ed ; h o we ve r , it is
k n o wn t ha t t h e y bi nd to a n d a ct i va te a n uc l ea r rec e pt o r (p e ro xi s o me p ro l ife r a t or – ac ti va t e d
r e c ep t or – γ [ P P A R -γ ] ) , w h i ch is e xp r e s se d i n m any i n su l in - se ns i ti ve ti ss ues , pr im a r il y a di po se
t i ss ue , bu t a ls o s ke le t al m us cl e a n d l i ve r t is su e . 16 0 P P A R -γ r eg ul a te s t r an sc r i pt i on of ge n es
t h a t i nf l ue n c e g l uc os e an d li pi d m e ta bo l ism . Fo r e xa m p l e P P A R - γ s ti mu l at i o n i nc r ea se s t he
t r a ns c ri p ti on o f G L U T - 4 , a g lu co se t ra ns p o rt e r t ha t st im u la t es g l uc os e u pta k e. I t is t ho u gh t t h at
r e d uc ed e xp r e ss io n of GL U T - 4 c on t r ib u te s t o t h e d e ve l op me n t o f i ns ul i n re s is ta nc e .
F u r t he r mo r e, TZ D s pr o mo t e a p op t os is o f la r ge adi p oc yt es a nd i n cr e as e t he n um be r of sm al l
a d ip o se c e ll s, wh i ch a re m o r e se ns i ti ve t o in s ul in a c ti on . In su l in - de p en den t gl uc os e u p ta k e i n
a d ip o se ti ss ue is i nc r e ase d an d l o we r r a te s o f l ipo l ys is , r e du ce f re e fa t t y a c id le ve ls , wh i ch
f u r t he r re d uc es in su li n re s is ta nc e i n m us cl e a n d l i ve r ti ss ue . 16 0 Th e TZ D s lo we r e xp r e s si o n o f
t u mo r ne c ro si s f ac t o r ( TN F ) - α , a c yt ok i ne p ro du ce d b y a d ip os e t is s ue wh ic h m a y c o nt r i bu t e t o
i n su li n re si s ta nc e a nd f at t y a ci d re le as e . 16 0 , 1 61 , 1 6 2 O th e r e f fe c ts o f TZ Ds t ha t m a y pr o ve to
b e be n ef ic i al i n p a ti e nt s wi t h m e ta bo l ic s yn d ro me a n d t yp e 2 di ab e te s i nc lu d e re du c ti on o f
i n f la mm at o r y m e di a to r s (e . g . , pl a sm in og e n ac t i vat o r in hi b it o r t yp e 1, C - r ea c ti ve p ro t ei n ) ,
i n hi b it i on of va sc ul a r smo o t h mu sc le ce ll p ro l if e ra t i on , i mp r o ve d e nd o th eli a l f u nc ti o n, β -c e ll
r e s to r a ti on , an d l o we r e d b l oo d p r es su r e . 1 6 1 , 1 63 , 1 6 4
Pharmacokinetics
R o s ig l it a zo ne is c om pl e te l y a bs o rb ed , wi t h p e ak p l as ma c o nc en t r at i on s re a ch e d i n
a p p ro xi m a t el y 1 ho u r ; f oo d do es no t a l te r it s a bso r p ti o n . Th e pl as ma el imi n a ti on ha l f -l i fe is 3
t o 4 h ou r s. 1 65 R os ig l it a zo n e i s e xt e n si ve l y me t abo l i zed in t he li ve r , m ai nly b y C YP 2 C 8 , a nd
c i rc u la ti n g m et a bo li t es ar e co ns i de r ab l y le ss po te n t th an t he pa r en t dr u g. R o si g li t a zon e i s
e xc r e t e d t wo - t hi r ds i n u r in e an d o n e - t hi r d i n f ec es as c o nj u ga t ed m e ta b ol it e s .
P i o gl i ta zo n e h as a bi o a va i la b il i t y o f 83 % , wi t h pea k p l asm a c o nc en t r at io ns r ea ch e d i n
a p p ro xi m a t el y 1 . 5 h ou r s; f o od do es no t al t e r i ts ab s o rp t io n . 1 61 , 1 66 , 16 7 Pio g li t a zon e ha s a
s e r um h a lf - li f e o f 3 to 7 h o u rs an d 1 6 t o 2 4 h o u rs f or i ts m e ta bo l it es . It is me t ab ol i ze d, ma in l y
i n th e l i ve r b y C YP 3 A 4 a n d C YP 2 C 8, in t o t wo ac t i ve m et a bo li t es . Ap p roxi m a t e l y 15 % to 30 %
o f t he do se is re co ve r e d i n th e u r in e as m et a bo l ite s , wi t h t he r em ai n de r exc r e t e d in t o t h e bi l e
e i t he r as u nc h a n g ed dr ug o r a s m et a bo li t es .
B e c au se th e a c ti on o f t he TZ D s r el ie s o n g e ne t ra n sc r ip t io n a nd p ro t ei n pr o d uc t io n , t he on se t
a n d d u ra t io n o f ac ti o n a re u n re la t ed t o t he pl as ma h al f -l i fe . Th e o ns e t o f th e i r e f fe ct oc cu r s i n
1 t o 2 we e ks , b u t ma xi m u m e f f ec ts m a y no t be se e n f o r 8 to 12 we e ks . 161 , 1 68
Th e TZ D s a r e p ri m ar i l y exc r e t e d vi a b il e i n t h e f ec es wi t h s ma l l am o un t s e xc r e t e d a s
m e ta b ol i te s i n t he u ri n e; t h e r ef o re , no do se ad j ust m en t s a r e r eq u i re d i n pa t i en ts wi t h re n al
f a i lu r e. A ll of t he TZ D s ar e e xt e n si ve l y bo u nd to s e r um a l bu mi n .
Ad verse Effects
Hepatotoxicity
Tr o g l i ta zo n e , t he fi r st TZ D t o be ap p ro ve d b y t h e F D A , wa s as so ci a te d wi th i di os yn c ra t ic
h e p at o xo c i t y l e ad i ng to h e p at ic fa i lu r e a nd de a th i n s om e p a ti en t s, wh i ch b e ca me ap p a re n t
d u r in g p os t ma r ke t in g s urve i l la nc e . Du r in g c li n ic al t r i al s, ap p r o xi m at e l y 1 . 9% o f t r og l it a zo ne t r e a te d p a ti e nt s e xp e r i en c ed as y m pt om a ti c, r e ver s i bl e e le va t io ns in li ve r t r a ns am i na se
( a l an i ne t ra ns am i na se [ AL T] ) l e ve ls th a t we r e g rea t e r t h an th r e e t im es th e n o rm a l va l ue s
( ve r s us 0. 6 % o f p la ce b o -t r e a te d p a ti e nt s ). I n co n tr a s t, el e va ti o ns i n l i ve r tr a n sa mi na s e le ve l s
o b se r ve d d u ri n g p r e- a ppr o va l c li n ic al t ri a ls f o r p io g li t a zon e an d r os i gl i ta zo n e (0 . 26 % a nd 0 .2 % ,
r e s pe ct i ve l y) we r e s im il ar t o p l ac eb o (0 . 25 % a n d 0 . 2 % ). 1 65 , 16 7 Two c as e r e p or t s o f
h e p at o to xi c i t y ha ve b ee n l i nk ed to r os ig li t a zo ne us e ; h o we ve r , li ve r i n ju r y m a y ha ve b ee n
c a us ed b y ot h er f ac to r s. 1 6 9 , 1 7 0 A r ec en t a n al ys is o f 1 3 cl i ni ca l t r ia ls o f ro s ig li t a zon e s h o w n o
e vi d e nc e o f h ep a to t o xi c it y. 1 7 1 Mo n i to r in g o f l i ve r f u nc t io n t es t s ( L F Ts ) is r e c omm e nd e d a t
b a se li n e, e ve r y 2 mo n ths f or t he fi r st ye a r o f t h er a p y, an d p e ri o di ca l l y t he r e a ft e r f o r
p i og l it a zo ne an d ro si gl i ta zo n e (s ee C on t r ai n di cat i o ns a n d P r ec a ut i on s ) .
Hematologic Effects
TZ D t h e r ap y m a y re su l t in sm al l d ec r e as es i n h em o gl o bi n a nd he ma t oc r it. Tr a n si e nt de c re as es
i n ne u t ro ph i l co u nt s o ccu r r e d i nf r e qu en t l y wi t h in t h e fi rs t 4 t o 8 we e ks o f TZ D t h e r ap y. S om e
h a ve at t r ib u te d t h es e o bs e r va ti o ns to a d il ut i on a l e f f ec t ( t hi s i s di sc us se d f u r th e r i n t h e
f o l lo wi n g s ec t io ns ) . 17 2
Vascular and Cardiovascular Effects
I n c re as es in pl as ma vo lum e (6 % t o 7 % ) a n d p e ri ph e r al ed em a (5 % t o 7 % ) , p os si b l y c a us ed b y
a n in c re as ed e nd o th el i al c el l p e rm e ab il i t y, h a ve b e e n r ep o r te d wi t h t h e TZ D s . 16 1 , 1 7 3 Th e
i n ci de n ce of pe r ip h e ra l ed e ma is g r e at l y in c re as ed wh e n TZ D s a r e u se d i n c om bi n at i on wi t h
i n su li n (~ 1 5% ) . 16 7
A l t h ou gh no C H F ha s b ee n o b se r ve d i n t h e cl i ni ca l t ri al s , p at i en ts wi t h Ne w Yo r k H e a r t
A s so ci a ti o n ( N YH A ) c l ass I II an d c la ss I V c ar d ia c s t at us ha ve no t be en stu d ie d . Th e re f or e ,
t h es e a g en t s sh o ul d n o t b e us ed in s u ch pa t ie n ts, a nd ca u ti on is s u gg es te d in pa t ie n ts wi t h
m i ld e r C H F . 16 5 , 1 6 7 A sm a ll nu mb e r o f p a ti e nt s ta k in g ro si gl i ta zo n e a nd p i og l it a zo ne ha ve
e xp e r i e nc e d mi l d t o m ode r a t e e d e ma du r in g c li n ic a l t r ia ls an d i n t h e p os tm a rk e ti n g p er i od .
Th u s , th es e a g en ts sh o ul d be us ed c a ut i ou sl y i n p a t ie n ts wi t h p r e -e xi s t i ng e de ma . Si x c a s es o f
TZ D - a s s oc ia t ed C H F , ma r k ed pe r ip h er a l e de ma a n d p ul m on a r y e d em a we r e re p o rt e d b y
K e r m an i a nd G a r g, 1 74 wh o s u gg es t ed t ha t t h es e a g e nt s b e u se d c au t io us ly i n pa t ie n ts wi t h
c h r on ic re n al in su f fi ci e nc y a nd im pa i r ed c a r di ac f u nc t io n (e . g. , le f t ve n t ric u la r d ys f un c ti on ) .
Weight Gain
D o s e - re la t ed we i g ht g ai n h as be e n s ee n wi t h r os ig l i ta zo ne a nd pi og l it a zon e . Th e c au se of
we i g h t ga i n is li ke l y du e t o fl u id r et e nt i o n an d f a t a cc u mu la t io n . Th e we i g ht g ai n a p pe a rs to be
a ss o ci at e d wi t h a n i nc rea s e i n p e ri ph e r al ad ip ose t is su e a lo n g wi t h a re du c ti o n i n vi sc e ra l
a d ip o si t y. 17 4
Contraindications and Precautions

T y pe 1 d ia b et es : B ec au se i ns ul in is re q ui r ed f o r th e i r a ct i on , TZ D s sh o ul d n o t b e u se d
i n pe op l e wi t h t yp e 1 d i ab e t es .
P . 5 0 -5 7

P r e - ex is t in g h e pa t ic d is ea s e: P io g li t a zon e a nd r os i gl i ta zo ne sh o ul d n o t be us e d i n
p a t ie n ts wh o se A L T is >2 . 5 ti me s n or m al . TZ D s s h ou l d b e d isc o nt i nu ed if t h e A L T is >3
t i me s n o rm al , i f s e ru m b il i r ub i n le ve l s b eg in t o r ise o r i f th e p a ti en t c om p la i ns of an y
s ym p to ms th a t co u ld be a t t r ib u te d t o h e pa t it is ( e.g . , fa t ig u e, na us e a, vo mit i n g,
a b d om in al pa i n, an d d a rk u ri n e) .

S e v e re C H F ( N YH A c l ass es I I I a nd I V) : S ee pr e vi o us di sc us si on .

P r e me n op a us al an ov u la to r y wo me n : TZ D s ma y ca u se r es um pt i on of o vula t i on an d
m e ns t ru a ti o n i n wo m e n wi t h p o l yc ys t ic o va r i an syn d r o me , p l ac in g s uc h pa t i en ts a t r is k
f o r an un wa n t e d p r eg na nc y. F o r t he sa me r ea so n , i t s us e t o s t im ul a te o vula t i on in
wo m e n wi t h po l yc ys t ic ova r i a n s yn d ro me is u n der i n ves t ig a ti o n. 1 68

H i s to r y o f h yp e rs e ns it iv i ty t o T Z Ds .

D r u g s me t ab o li ze d b y CY P 3 A 4 : S e e D r u g I nt e r ac t io ns in t he ne xt s e ct i on f o r f u rt h e r
d e t ai ls .
Drug Interactions
P i o gl i ta zo n e i nd uc es th e h e pa t ic m ic r os om al en zym e C YP 3 A 4 , a n d t hi s is t he un de r l yi ng
m ec h an is m f o r i ts es ta b lis h ed in t e ra ct i on s wi t h est r o g en s a nd te r f en a di ne . Th e r e f o re , o n e
s h ou l d b e a le r t f o r p o te nt i a l d ec r ea se d e f fe c ti ve ne ss o f o th e r d r ug s m et a bo l i zed b y th is
e n zym e , s uc h a s c ycl os po r i ne , ta c ro li mu s , a nd 3 -h yd r o xy - 3 - m e t h yl -g l ut a r yl - c oe n zym e A ( H MG C o A ) r ed u ct as e i n hi bi t o rs . R os ig li t a zo ne do es not a pp e a r t o i nh i bi t a n y of t h e m aj o r C YP
e n zym e s.
Glyburide
C o a dm i ni st r a ti on o f g l ybu r i de wi t h a TZ D d o es no t al t e r t he ph a rm ac ok i ne t ic s o f e i th e r d r ug ,
b u t m a y in c re as e t h e p ati e n t 's ri sk fo r h ypo g l yc em i a.
Oral Contraceptives
Tr o g l i ta zo n e r e du ce d p l as ma co nc e nt r a ti on s o f o ra l c o nt r ac e pt i ves co n ta ini n g e t hi n yl e st r a di ol
a n d n o re t hi n d ro ne b y 30% . A lt h ou g h t he ph a rm ac ok i ne t ics o f o r al c o nt r ac e pt i ves wh e n
c om b in e d wi t h pi o gl i ta zon e ha ve no t b e en e val u at e d , t h e ma n uf ac t u re r c au t i on s a ga i ns t t he i r
c o nc om it a nt us e . B ec a use l oss o f co n t ra ce p ti ve ef f i ca c y i s p os si bl e , a dd i tio n al o r a lt e r na t i ve
m e th o ds s h ou ld be co ns id e r ed . 16 7 Al t ho u gh th e re h a ve b ee n n o s t ud ie s o f in t e ra ct i on s wi t h
e s t ro g en r ep la ce me n t p ro d uc ts us e d b y po s tm eno p a us al wo m en , o n e s hou l d b e a le r t fo r
r e c ur r i ng s y m p to ms o f es t r og e n d ef ic i en c y. Ro sig l i ta zo ne d oe s n ot af f ec t t h e p ha r ma co ki n et ic s
o f o ra l c on t r ac ep t i ves , su g g es ti n g t ha t ro si g li t a zo n e m a y n o t i n te r ac t wi th o th e r d r ug s
m e ta b ol i ze d b y th e C YP 3 A 4 is oe n zym e.
Efficacy
Th e e f f ec ts of TZ D s o n A 1 C a nd F P G a r e i n te r med i a te be t we e n t h a t o f aca r b os e a nd t he
s u lf o n ylu r ea s o r m e tf o rmi n . 47 , 16 3 W hen c o mb in ed wi t h o th e r a n ti di a be t ic a g e nt s i n a p o o rl y
c o nt r o ll ed t yp e 2 p a ti e nt , o n e ca n e xp e c t to se e an a ug me n te d e f fe c t o n t he A 1 C (0 . 9% t o 1 .3 %
d e c re as e wi t h a s ul f on ylu r e a , 0 .8 % t o 1 . 2% de c re a se wi t h m e tf o rm i n, and 0 .6 % to 1. 0 %
d e c re as e wi t h i ns ul i n) 1 65 , 1 67 ( al so s e e Q u es t io n 5 8 ) . W hen a d de d t o th e t h e r ap y o f a t ype 2
p a t ie n t t ak in g i ns u li n , r os i gl i ta zo ne a nd pi og l it a zo n e c an en h an ce gl yc emi c c on t r ol wh i l e
d e c re as in g i ns u li n re qu i re m en ts ( se e Qu es t io n s 59 a nd 63 ) .
O t h e r po t en t ia l b en e fi t s o f t he TZ D s a r e t h ei r fa vo r a bl e , b u t va r ia b le , e f f ec t s o n l ip id s :
p i og l it a zo ne de c re as es tr i g l yce r id e l e vel s b y ~ 9% a nd bo t h p io gl i t zao n e a n d ro si gl i ta zo n e
i n c re as e H DL le ve ls b y ~1 5 % t o 2 0 %. 1 61 R os ig l ita zo n e h as no e ff ec t o n tr i g l yce r id e l e vel s ,
a l t ho ug h f re e f a tt y a ci d le ve l s a r e d ec r ea se d b y u p to 22 % . 1 6 1 P i og li t a zon e ha s l it t le o r n o
e f f ec t o n L D L c h ol es t er ol l e vel s, bu t ro si g li t a zone is as so ci a te d wi t h a 1 0% t o 1 4% in c re as e i n
t h es e val u es . 16 5 , 1 67 Th is in c re as e i n L D L c h ol est e r ol ma y b e d ue t o a s hi f t f r om s ma ll e r ,
d e ns e p a r ti cl es to la r g er, m or e b u o yan t on es , whi c h a r e l ess su sc ep t ib le to
o xi d a t i on . 1 61 , 16 3 , 1 7 5 Th e r a p y wi t h a l l o f t he TZ D s ha s b e en ass oc i at e d wi t h we i gh t g a in an d ,
wh e n u se d i n c om bi n at i on wi t h su l fo n ylu r e as o r in s ul in , we i g ht ga i n ca n be su bs t a nt ia l (1 . 8 t o
5 . 4 k g o r 4 t o 1 2 p ou n ds) . 1 6 5 , 1 67 A no t he r i n te r es t in g o bs e r va ti o n is t ha t a p p ro xi m a t el y 2 5% o f
i n di vi d ua ls t re a te d wi t h TZ D s a r e u n re sp o ns i ve . A l t h ou gh t he re a so n i s un k no wn , t h es e
i n di vi d ua ls a re le ss l ik e ly t o b e o be se an d h a ve lo we r i n su li n a n d C - p ep t id e le ve ls ,
e m ph as i zi ng th e f a ct th at t h e TZ D s wo r k o n l y i n in d i vid u al s wi t h e nd og e no u s i ns ul in . 1 72
Dosage and Clinical Use
A g r ea t e r g lu co se - l o we r in g ef f ec t h as be e n o bs e rve d wh e n r os ig li t a zo ne is gi ve n a s t wo
d i vi de d d o se s r a th e r t h an as a s in gl e d a il y d os e. F o r m on o th e r ap y, a t yp ic a l d os e is 4 m g o nc e
d a il y o r 2 mg t wi c e d ai l y, r e g ar d le ss of m e al s. I f th e r es po ns e i s i na d eq uat e , th e d os a ge c a n
b e in c re as ed t o 8 m g o nc e d a il y o r 4 m g t wi ce dai l y. Fo r co mb in a ti o n t he ra p y wi t h a
s u lf o n ylu r ea , m e tf o rm i n, o r in s ul in , ro si g li t a zon e c a n b e i ni t ia t ed at 4 m g o n ce da il y. O n l y
d o se s o f 8 m g h a ve be en s tu di e d i n co mb i na t io n wi t h m et f o rm in . 16 1 , 1 6 5
F o r m o no t he r ap y wi t h p io g li t a zon e , t h e d os e is 15 mg o r 3 0 m g o nc e d ai ly wi t h o r wi t h o ut fo o d,
wh i c h ca n b e i nc r ea se d to a m a xi m um of 45 mg da i l y. F o r c om bi n at i on th er a p y wi t h a
s u lf o n ylu r ea , m e tf o rm i n, o r in s ul in , p i og li t a zo ne ca n be in i ti a te d a t 1 5 o r 30 mg on ce d ai l y. No
p l ac e bo -c o nt r o ll ed cl in ica l s t ud i es o f >3 0 m g p iog l i ta zo ne h a ve b ee n c ond u ct e d t o d a te wi t h
c om b in a ti o n t he r ap y. 1 6 7
A l t h ou gh r os ig l it a zo ne an d pi og l it a zo ne ca n b e us e d as in i ti a l t he r a p y f o r n e wl y d i ag n os ed t ype
2 d ia be t es , c os t o f t en lim i ts th e ir us e t o p a ti e nt s wi t h c on t r ai nd ic a ti o ns to su l fo n yl u re as o r
m e t fo rm i n o r t o th os e who ca n no t to le r a te si de e ff e c ts a ss oc ia t ed wi t h th e o t he r ag e nt s . A ll o f
t h e TZ D s c an be us ed in c om bi n at i on wi t h o t he r a g e nt s i n u nc on t r ol le d t yp e 2 d ia b et es
p a t ie n ts (s ee Q u es ti o ns 5 0 , 5 8 , a nd 63 ) .
Treatment of Patients With Type 2 Diabetes
Clinical Presentation
L . H . is a 4 5 - ye a r - o l d mo d e r a te l y c e n t r a l l y o b e s e ( he i g ht , 5′ 5 ″ ; w e i g h t, 1 60 l b ; B M I 2 6. 6
k g / m 2 ) Me x ic a n - Am e r i ca n w o ma n , w ho w a s r e fe r r e d t o t h e d ia b e te s c li n i c w he n h e r
g yn e c o l o g i s t, w h o h a d b e e n t r e a ti n g h e r fo r r ec u r r e n t m o ni l i al i nf e c tio n s , n o t ed
g l u c os u r ia o n r o u t in e ur i n a l ys i s . S u b s e qu e n tl y, o n tw o s ep a r a te oc c as i o ns s he w a s
f o u n d t o ha ve a n F P G of 1 5 0 m g/ d L a n d 1 67 mg / d L . L . H . d e ni e s a n y s ym p t o m s o f
p o l yp h a g i a o r p o l yu r i a , a l t h ou g h l a te l y s h e h as b ee n m o r e th i r s t y t h a n u s ua l . S h e d o es
c o m pl a i n o f l e t ha r g y a n d o f te n ta k es a ft e r n oon n a ps .
L . H . ' s o t he r m ed i ca l p ro b l em s in c lu d e m i ld h yp e r t e ns i o n, w h ic h is w e l l co n t r ol l e d o n
l i s i no p r i l 2 0 m g /d a y, a n d r e c u r re n t m o n il i a l i n fe c t i on s , w hi c h a r e t r e at e d w i t h
f l u c on a zo l e. S he h as
P . 5 0 -5 8
g i ve n b i r th t o f o u r c h i ld r e n ( bi r t h w ei g h ts , 7, 8 . 5 , 1 0 , a nd 11 l b, r e spe c t i ve l y) a n d w a s
t o l d du r i n g h e r l a s t p r eg n a nc y t h a t s h e h a d “ bo r d e r l i ne di a be t e s. ” S he c u r r en t l y w o r k s a s
a l o an o f fi c e r i n a l oc a l b a nk a nd sp e n ds he r w e ek e nd s “ ca t c hi n g u p o n he r s le e p” a n d
r e a d i ng . L. H . ha s b e en s m o ki n g o n e p ac k of c ig a r e t t es / da y f o r 2 0 ye a r s a n d d r i nk s a n
o c c as i on a l g l as s o f w i ne . H e r fa m il y h i s t o r y i s s i g n i fi c an t f o r a s i s te r , a u n t , a nd
g r a n d mo t h e r w i t h t yp e 2 d i ab e te s ; a l l h a ve “w e i g h t p r o b le ms . ” L . H .' s m o t he r i s a l i ve a n d
w e ll a t a ge 77 ; h e r f a the r d i ed o f a he a r t a t t ack a t a g e 4 7.
L a b o r at o r y a s s e ss m en t r e ve a l s a n F P G o f 1 4 7 m g / d L ( n o rm a l , 7 0 t o 10 0 ) ; f a s t in g pl a sm a
t r i g l yc e r i d e s o f 40 0 m g/ d L ; a n d a n A 1 C o f 9 . 2 % ( n o r ma l , 4 % t o 6 %) . Al l o t h e r va lu e s
( i n c l ud i ng t he c om p le te b l oo d c o u n t [ C B C ] , e le c t r o l yt e s , l i ve r f u n c ti on t e s ts , a n d re n al
f u n c t io n te s t s) a r e w i t hi n n o rm a l l i mi t s . L . H . i s g i ve n t he d ia g no s is o f t yp e 2 d i a b et e s.
W h a t fe a t u re s i n L. H . ' s h i s t o r y a n d p h ys i c a l e xa m i na t i on a r e c on s is t en t w i t h th i s
d i a g no s is ?
[ S I un i ts : p l asm a g l uc ose , 8 .3 , 9 . 3, an d 8 . 1 mm ol / L ; p la sm a t r ig l yce r i de s, 6 . 77 mm ol / L; A 1 C ,
0 . 0 9 ( n or ma l , 0 . 04 to 0 .07 ) ]
Th e f e a tu r es o f L. H . ' s h is t o r y th a t a r e co ns is t en t wi t h t yp e 2 d ia be t es in clu d e a n F P G
c o nc en t r at i on of ≥ 12 6 mg / d L o n mo r e t h an on e oc ca si o n, a n el e va t ed A 1 C , h ig h B MI wi t h
c e nt r a l o be si t y, ag e g r eat e r th a n 4 0, f am il y h is to ry o f d ia be t es , a n d Me xi c a n Am e ri c an
d e sc en t . L . H . a ls o h as de l i ve re d l a rg e ba bi es , wh i ch s u gg es t s t ha t s h e ma y h a ve ha d
u n di a gn os e d g es t at io n al d i ab e te s, a c on di t io n tha t pl ac es wo m e n a t h ig h r i sk fo r su bs eq u en t l y
d e ve l op in g t ype 2 d ia be te s . Di ag n os is on ro u ti n e e xa m i n a ti o n a nd m il d s i gn s a n d s ymp t om s o f
h yp e r gl yc em i a ( in cl u di ng i nc r e as ed th i rs t a n d l et ha r g y) , r ec ur r e nt mo ni l ia l i n f ec ti o ns ,
h yp e r t ri g l yc e r id em ia , and i nd ic a ti on s o f c a rd i o vas cu l a r d is ea se (m il d h ype r t e ns io n ) a ls o a r e
t yp i ca l i n p a ti e nt s wi t h t yp e 2 d ia b et es (s e e Typ e 2 D i ab e te s a nd Ta b le 50 - 1 ) .
Treatment Goals
W h a t s h o ul d th e go a l s o f t h e ra p y b e f o r L . H. an d o t he r pa t i en t s w i th typ e 2 d i a b e te s ?
W h i c h b i oc h em i ca l i n d ic e s s h ou l d b e m o n i to r ed ?
Th e b e gi nn i ng of t hi s cha p t e r d isc us se d g e ne r al g o al s o f th e ra p y f or al l pe o pl e wi t h d i ab e te s,
wh i c h in cl u de el im in a ti ng ac u te s ym p to ms of h ype r g l yce mi a , a vo id in g h yp o g l yce mi a , r e du ci ng
c a r di o vas cu l ar r isk f ac tor s , a n d p r e ven t in g o r s l owi n g t h e p r og r es si on o f b o t h mi c ro va sc ul a r
a n d m ac r o vas cu la r di ab et i c c om pl ic a ti on s . Th e AD A r e co mm en ds t ha t o t he r wi s e he al t h y
p a t ie n ts wi t h t yp e 2 di a be t es st r i ve t o a ch i e ve t he sa me bi oc h em ic al go a ls as th os e
r e c omm e nd e d f o r p eo pl e wi t h t yp e 1 di a be t es 73 , 93 ( se e Ta bl es 50 - 5 a n d 5 0 - 11 ) .
Th e U K P D S wa s t he lo ng e st an d l a r ge st st u d y o f p a ti e nt s wi t h t yp e 2 di ab e t es . I t c o nc lu si ve l y
d e mo ns t r at e d t ha t im pr ove d b lo o d g lu co se c o nt ro l re d uc es th e ri sk o f deve l o pi n g r e ti n op a th y,
n e p hr o pa t h y, a n d p ot e nt ia l l y, n e u ro pa t h y. 22 A 2 5% o ve r al l r e du ct i on in m ic r o vas cu l a r
c om p li ca t io n ra t e wa s obs e r ve d i n t ho se pa t ie n ts r e c ei vi ng in t en si ve t he r ap y ve r s us
c o n ven t io n al th e ra p y. A n a d di t io na l fi nd i ng of t he U K P D S wa s t ha t ag g re ss i ve c on t r ol of B P
a l so s i gn i fi ca n tl y r e du ced s tr o ke s, di a be t es - re l ate d de a th s, he a r t f a il u re , m ic r o vas cu l a r
c om p li ca t io ns , a n d vi si on l oss . 17 6 , 17 7
W hen d et e rm i ni ng t re a tm e nt go a ls fo r L . H . a n d o t h e rs wi t h t yp e 2 di a be te s , t h e sa me
i n di vi d ua l c ha r ac t e ri st ic s s ho u ld be c o ns id e r ed as f or t yp e 1 d i ab e te s, suc h a s t h e p at i en t ' s
c a pa ci t y t o u nd e rs t an d an d c a r r y ou t th e t r ea t men t r eg im e n, th e p a ti e nt ' s r i sk fo r s e ve re
h yp o g l yc em i a, an d o t he r p a ti e nt - sp ec i fi c f ac t o rs th a t m a y in c re as e t h e r isk o r d ec r ea se th e
b e n ef i t o f i nt e ns i ve t r ea tm e nt ( e. g . , a d van ce d a ge , E S R D , a d va nc ed ca r di o va sc ul a r o r
c e r eb r o vas cu la r di se as e, o r o t he r co e xi s t in g d is ea s es th a t ma y s ho r t en li fe e xp e c t an c y) .
E m p ha si s sh o ul d b e p l ace d on as se ssm e nt o f a ll c a r di o vas cu l ar r isk f ac tor s , i nc l ud i ng
h yp e r t en si on , to b acc o us e , d ys li pi d e m ia , a n d f am i l y h is t o r y.
Ma c r o va s cu l a r d is ea se is t he pr im a r y ca us e o f de a t h i n t hi s p op u la t io n , an d it s u nd e r l yin g
p a t ho g en es is m a y o r m ay n o t be re l at e d t o h yp e rg l yc em ia pe r s e . Thi s i s a su b je ct o f g r ea t
c om p le xi t y a n d c o nt r o ver s y. A l th ou g h t he p re va le n ce of ca r di o vas c ul a r m o r bi di t y a nd m o r ta li t y
c o r re l at es wi t h A 1 C l e vels in ob se r va t io n al an d ep i de mi o lo g ic s tu d ie s , n o p r o sp ec t i ve,
r a n do mi ze d , c on t r ol le d t ri a ls ha ve es ta b li sh e d a re l a ti on sh i p b et we e n ma cr o va sc u la r di se as e
a n d t h e d eg r ee o f g l yc em ic co n tr o l. 2 0 , 1 34 W heth e r i n t en si ve in su li n th e ra p y is ap p r op r ia t e f o r
p e o pl e wi t h t yp e 2 di ab et e s a ls o h as be e n q ue st io n e d. S om e h a ve wo r r i ed t ha t
h yp e r in su l in em i a as so cia t e d wi t h in t en si ve in s ul in t he r a p y o r th e s ul f on ylu r e as ac tu a ll y co u ld
a cc e le r a te at h e ro sc le r osi s o r in c re as e t h e r is k o f c a rd i o vasc u la r e ven ts . H o we ve r , t h e U K P D S
s h o we d n o i nc r e as e i n ca r d io va sc ul a r e ve n ts o r m o r ta li t y i n p at i en ts as sig n e d t o su l fo n yl u re a
o r in s ul in th e r ap y, de s pi te t he i r f as t in g p l asm a i ns u li n l e vel s b ei n g h ig h er t h an t ho se of t he
c o n ven t io n al l y t re a te d pa t i en ts . 22 Th e r e is al so c o nc e rn th a t t h e co u nt e r - r e g ul a to r y h o rm on es
t h a t a r e r e le as ed in r es po n se to h yp og l yce mi a a ls o c ou l d e nd a ng e r t h os e wi t h e xi s t i ng
c a r di o vas cu l ar di se as e . Th e s e vie ws a r e s umm a ri ze d an d a n al yze d b y C ol we l l 1 78 , 17 9 a n d
o t h e rs ,1 8 0 wh o s ug ge s t t a ki n g a m o re ag g r ess i ve s ta nc e t o wa r d gl yc em ic co n t ro l t ha n th a t
wh i c h ha s b ee n p r e vi ou sl y p r ac t ic ed as we l l a s a tt e n di ng t o t he r ed uc t io n o f al l ri sk fa ct o rs fo r
c a r di o vas cu l ar di se as e (e . g . , h yp er t e ns io n , d ysl ip i de mi a , p la t el e t h yp e r - re a ct i vi t y,
m ic r o al bu mi n u ri a ).
Mo s t a g r ee t ha t g l yce m ic go a ls fo r p a ti e nt s wi t h t yp e 2 d ia b et es mu st be i n di vi d ua li ze d . F o r
e xa m p l e , a d van ce d a g e o r si g ni fi c an t c e re b ro va sc u la r or co r on a r y a rt e r y d i se as e s ho u ld be
c o ns id e re d re l at i ve c on t ra i nd ic a ti o ns to in t en si ve c o nt r o l i n t yp e 2 d i ab e tes be ca u se of th e
s e r io us c o ns eq u en ce s o f h yp o gl yc em ia ; ho we ve r , m an y t r e at me n t o pt i on s a va i la b le to d a y ar e
a ss o ci at e d wi t h a ve r y l ow r i s k of h ypo g l yc em i a.
B e c au se L. H . is re l at i ve ly yo u n g an d h as no s ymp t om s o f m ic r o vas cu la r d i se as e o r
n e u ro p at h y, e ve r y e f f or t s h ou l d b e ma d e t o n o rma l i ze h e r g lu co se co nc e nt r a t io ns to a voi d
t h es e m o rb i d e ve nt s . F u rt h e rm o re , a l ip id pa n el sh o ul d b e or d e re d a nd ste p s t ak e n t o ac h ie ve
n o r ma l L D L c ho l es te r ol , H D L c ho le s te r ol , an d t r igl yc e r id e l e vel s . O f t en , t rig l yc e ri de le ve ls
i m p ro ve as b l oo d g l u c ose co nc e n tr a ti o ns d ec l in e a n d t he me t ab ol ic r es pon s e t o i ns ul i n
i m p ro ve s. ( Ma n a g e - me n t o f d ys l ip id em i a is ad d r es se d m o re f ul l y l a te r in th i s ch a pt e r . )
B i o ch em ic al in d ic es th a t s h ou l d b e f ol lo we d t o m on i t or L . H. ' s re sp o ns e t o th e r ap y i nc lu d e
f a s ti ng , po s t p r an di a l a nd p r e pr a nd i al bl oo d g l uc os e c on c en t ra t io ns , A 1 C va l ue s , f as t in g
t r i gl yc e ri d e l e vel s, an d LD L a nd H D L c ho l es te r ol c o nc en t r at i on s. I ni ti a l me t a bo li c g o al s f o r
L . H . s h ou l d b e a n A 1 C val u e
P . 5 0 -5 9
o f <7 % , a n F P G < 13 0 mg / d L, a p os t p ra nd i al gl uco s e co n ce n tr a ti o n o f < 1 80 mg / dL , an d
t r i gl yc e ri d e l e vel s o f < 1 50 mg / dL .
Lifestyle Interventions
H ow s h o ul d L. H . be man a g ed i ni t i a ll y?
I n i ti a l t he r ap y o f t ype 2 d i ab e te s i s a im ed at li f es t yl e c ha n ge s t ha t wi l l mi n im i ze i ns ul i n
r e s is ta nc e a n d r is k f o r ca r d io va s c ul a r d is e as e. In L . H . 's c as e an d i n t h e c as e o f ot h e r
o ve r we i g h t (B MI 2 5 . 0 to 2 9 . 9 ) o r o be s e ( B MI 3 0 . 0 a n d a bo ve ) , t ype 2 i nd i vi d ua ls , th is in cl u de s
a l o we r - ca lo r ie , lo w - f a t an d c h ol es t e ro l d ie t ; re gu la r e xe r c is e ; sm ok i ng c ess a ti o n ( se e Ch a pt e r
8 5 , To ba cc o Us e a nd D ep e n de nc e ) a nd ag g r ess ive m an a ge me n t o f d ys li pi d em ia an d
h yp e r t en si on . B ec au se ob e si t y is ass oc i at e d wi t h i nc r e as ed ti ss ue r es is t an c e t o e nd o ge n ou s
i n su li n , L . H . s ho ul d b e s tr o n gl y e nc ou r a ge d t o d ec r e as e h e r ca l or ic in t ak e a n d l os e we i g h t.
W hen si g ns a n d s ymp t om s a r e mi l d, di e t a nd e xe r c is e a lo ne ca n c o rr e ct g l uc os e i n to l er a nc e.
S MB G m o n it o ri n g sh o ul d b e e nc o u ra g ed an d e duc a ti o n t ha t ad d re ss es the se r i ou s n at u r e o f
d i ab e te s m el li t us an d i ts l o ng - t er m c on se q ue nc es al so sh o ul d b eg i n. Th is i s d is cu ss ed in th e
p r e vi ou s s ec ti o ns , Me d ica l N ut r i ti o n Th e r ap y a nd E xe r c i s e , u nd e r Tr e at men t ( al so s e e Ta b l e
5 0 - 16 ) . Ta bl e 5 0 - 32 s umm a r i zes a ss es sm en t a n d p h a rm ac ot h e ra p y c o un se l in g p o in ts f o r
p a t ie n ts wi t h t yp e 2 di a be t es .
Self-Monitored Blood Glucose in Type 2 Diabetes
L . H . is i n te r e s te d i n le ar n i n g how t o p e r f o rm bl o o d g l u co s e t es t i n g. W h a t a r e th e
a d va n t a ge s a n d d i sa d va n t a ge s o f SM B G t e s ts? W h en an d how o f t en s h o u ld L . H. b e
i n s t r uc t e d t o te s t h e r bl o o d g l u co s e c on c en t r at i o n s?
D a i l y pe r f or m an ce of S MB G i s i mp o r ta n t f o r p at i en t s s uc h as L . H. t o as ses s t h e e f fi ca c y o f
t h e r ap y a nd gu id e a d ju s tm e nt s i n n u tr i ti o n, e xe r c is e , a nd me di c at io n s. P e rf o r mi n g S MB G a l s o
h e lp s t o m on i to r fo r an d p r e ve n t h yp og l yce mi a . D i s ad va n ta g es i nc l ud e c os t of te s ti ng ,
i n ad e qu a te un d e rs ta n di ng b y bo t h h ea l th ca r e p ro vi d e rs an d p a ti en t s r e ga r d in g th e b en e fi t s
a n d p r op e r u se o f S MB G r e su l ts , p a ti en t ps ych o lo g ic al an d ph ys ic al di sco m fo r t a ss oc i at e d wi t h
o b t ai ni n g a b l oo d s am ple , an d th e i nc on ve n ie nce o f t es t in g . H o we ve r , wi t h t he c u r re n t
a d va nc es in me t er t ec hno l og y a n d p ro p e r p at i en t e d uc at i on , m os t o f th ese p ot e nt i al ba r r ie r s
c a n b e o ve rc om e .
Th e A D A r ec om me n ds SMB G f o r a ll pa t ie n ts t a kin g in su li n , b u t i ts s t an ce wi t h r e ga r d t o t ype 2
d i ab e ti cs t re a te d wi t h d ie t o r d ie t p l us o r a l a ge n ts is le ss c le a r . 7 3 Th is i s b ec a us e s e ve ra l
s t ud i es e va l ua t in g t h e e ff e c t o f S MB G i n p e op le wi t h t yp e 2 d ia be t es ha ve sh o wn n o e f fe c t o n
g l yc em ic c o nt r ol . 18 1 N eve r t h e le ss , t h e A D A do es su gg e st th a t t h e “ o p t ima l f re q ue nc y a nd
t i mi n g o f S MB G f o r p a ti en t s wi t h t yp e 2 di ab e te s i s n o t k no wn b u t s ho ul d b e s u f fi ci en t to
f a ci l it a te r ea ch i ng gl uc os e g o al s. ” 7 3 W e o f te n rec om me n d S MB G f o r m o tiva t e d t ype 2 p at i en ts
wh o a r e le a rn i ng to ad j us t th e ir ca r bo h yd r at e i n ta k e a nd wa n t to m e as u re h o w we l l me di ca t io ns
a n d l i fe st yl e c h a n ge s a re wo r k i ng to im p ro ve th ei r gl uc o se c o nt r ol . In i ti a lly, we m a y s ug g es t
t e s ti ng f ou r ti me s d ai l y be f o r e me a ls a n d a t b ed t im e fo r 1 we e k s o t h at the p at i en t c an ob s er ve
h i s o r h e r g lu co s e p ro f il es . La t er , on ce th e d e si r ed A 1 C h a s b ee n a ch ie ve d, we r e c omm e nd a
m i ni mu m o f t es t in g g l uc os e c on c en t ra t io ns t wi c e d a il y, b ut a t va r io us t im es t o e va lu a te fa s ti ng
g l uc os e c on ce n t ra t io ns , 2 - h ou r po s tm ea l c on ce n tr a t io n s, an d p r ep r a nd ia l c o nc en t r at i on s. A
s t ud y o f t ype 2 p at i en ts tr e a t ed wi t h d i et wi t h or wi t h o u t o r a l a ge n ts , b u t n o t i ns u li n , o bs e r ved
t h a t 2 - ho u r p os t lu nc h valu e s ( < 15 0 m g/ d L ) a nd p re d in n e r va l ue s ( < 12 5 m g/ d L ) m os t c lo se l y
c o r re l at e d wi t h A 1 C val u es o f < 7% . 18 2 As e mp h asi ze d b y th e A D A, in t en sive p a ti e nt ed uc a ti o n
r e g a rd i ng te st i ng te c hn iqu e an d i n te r p re t at i on a re vi t a l t o t h e co s t -e f fe ct i ve us e o f th is
m o ni t o ri ng t oo l. Th e pa t ie n t m us t b e a b le to as ses s h is o r h er gl uc os e pr of i l e a nd in st i tu t e
l i f es t yle ch an g es th a t can h a ve a fa vo r ab l e e f fe ct.
Treatment: A Stepped-Care Approach
L . H . w a s q u it e m o t i va t ed t o im p r o ve he r g lu c os e co n t r o l b ec a us e h e r g r a n d mo t h e r “ lo s t a
l e g ” t o d i a be t es an d her a u n t i s u n d e rg o i ng d ia l ys i s b e ca u se “h e r k i dn e ys h a ve f a i le d .”
S h e me t w i t h a d i e t it i an w h o su g ge s t ed an 1 ,80 0 - ca l o r ie d ie t an d 4 5 m i n u te w a lk s th r e e
t i m e s w e ek l y. Af t e r 3 m o n t h s, L . H . h ad l os t 6 po u n d s. Al t h o u gh h e r FP G f e l l to 13 0 m g / dL
( n o r m al , 70 t o 1 00 ) , > 5 0% o f h e r p o s t p ra n d ia l bl o o d g l u co s e l e ve ls w er e o f t en >1 8 0 m g /d L
( n o r m al , <1 4 0) . H e r A 1 C i s 8. 0 % ( n o r m a l , 4 % t o 6 %) , a n d f as t i n g t r i g l yc e r i de l e ve ls a re
n ow 2 60 mg / d L ( n o r ma l, < 15 0 ) . T h e ra p y i s t o b e i n i ti a te d w i t h a n o r a l a n t i d ia b et i c
m e d ic a t io n . W h a t f a ct or s s h ou l d b e c o ns i d e red w h e n d e ci d i ng o n a n a g e n t?
S e l ec t in g a n o r al ag e nt to t r ea t t ype 2 d ia b et es ha s b ec o me m o re co mp l ex a s n e w a g e nt s wi t h
u n iq u e m ec ha ni sm s o f ac t io n h a ve b e en in t r od uce d in t o t he ma rk e t . A s wit h al l t h e ra p eu ti c
d e ci si o ns , cl i ni ci a ns m ust b le n d t he i r k no wl e d ge o f t he dr u g ( e .g . , i ts e ff ic ac y, sa f e t y, d os in g
m e th o ds , a n d co st ) wi t h t h e u n iq u e ch a ra c te r is t ics o f t he pa t ie n t ( e .g . , l e ve l of gl yc em ic
c o nt r o l, o rg an f un ct i on , o t h e r co nc u r re n t d is ea s es an d m ed ic a ti o ns , a bi l ity t o a dh e re t o
c om p le x m e d ic a ti on r eg im e ns , h ea l th ca r e c o ve ra g e ) wh e n ma ki n g a c ho ic e o f dr u g p r od uc t s.
W e, l ik e o t he r s , su g ge st a s te p wi s e ma n ag em e nt a p p ro ac h to a voi d u n ne ce ss a r il y co mp l e x
t h e r ap y t ha t m a y co n fu se t he pa t ie n t , i nc re a se dr u g c os t s, an d c om pl ic a te t he cl in ic i an ' s a bi l it y
t o as se ss e a ch m e di ca t io n ' s c on t r ib u ti on t o t he ove r a l l t h er a pe u ti c o ut c om e 18 3 , 1 8 4 , 1 85 ( Fi g .
5 0 - 9 ).
A f t e r i ns t it u t i n g a pp r o pr ia t e l i fe st yl e c h an ge s , we r e co mm en d m on o th e r apy f o l lo we d b y
c om b in a ti o n t he r ap y wi t h t wo o r a l a ge n ts if th e r ap e u ti c g oa ls a re no t m e t. I f pa t ie n ts fa il
t h e r ap y wi t h t wo o r al age n ts , on e c ou ld mo ve to t r i pl e o r a l t he r a p y o r t rea t wi t h a si n gl e o r al
a g e nt pl us in su li n . To a vo i d i nj ec t io ns , m a n y p a tie n ts an d c a re g i ve rs o p t fo r t r ip le co mb in a ti o n
t h e r ap y ( us i ng or a l a ge nt s wi t h d i ff e r en t m ec ha n is ms of ac t io n ), bu t th is is ha s n o t b ee n
s t ud i ed e xt e n si ve l y, wi t h p u bl is he d s t ud i es c on sis t in g o f s ma l l t r ea tm e nt
g r o up s . 1 86 , 1 87 , 18 8 , 1 8 9 O n e st u d y c om p ar e d t r ipl e or a l t he r a p y wi t h i ns uli n 70 / 30 Mi x p l u s
m e t fo rm i n i n p at i en ts wi t h t yp e 2 di ab e te s p o or l y c o nt r o ll ed on t wo o r al age n ts . 19 0 Al t ho u gh
b o t h t r ea tm e nt s we r e a bo u t e q ua ll y e f fe c ti v e in lo we r i n g A 1 C a nd F P G valu e s ( 1 .7 7 %; 55 mg / dL
a n d 1 . 96 % ; 6 5 mg / dL , r es p ec ti ve l y) , 10 . 2% of pa ti e n ts i n t h e t r ip l e - t h er a py g r o u p we r e
s wi t c h ed to th e i ns u li n p lu s m e tf o rm in t he r ap y b ec a us e o f i na d eq u at e re sp o ns e ; h o we ve r ,
t h es e p a ti e nt s h a d hi g her A 1 C
P . 5 0 -6 0
P . 5 0 -6 1
l e ve ls ( a ve: 10 . 6% ) at bas e li ne . Th e c os t o f t ri pl e t h e ra p y ( d ru g c os t p lu s L F T m o ni to r i ng fo r
t h e TZ D s ) wa s hi g he r .
Table 50-32 Assessment and Counseling Points: Type 2 Diabetes
For All Patients






Educate about symptoms of hyperglycemia, including frequent urination, excessive
thirst, unexplained weight loss, fatigue, and recurrent infections, which signal
inadequate control.
Educate about symptoms of hypoglycemia, including hunger, anxiety, rapid heart
rate, sweatiness, morning headaches, and restless sleep. Skipped meals can
predispose to hypoglycemia. May occur when antidiabetic agents are used in
combination.
Encourage patients to follow blood glucose concentrations according to SMBG
(self-monitoring of blood glucose). Review goals. Help patients interpret levels in
context of diet, exercise, and drug therapy. Periodically review patients' technique
for appropriate meter use.
Reinforce principles of diet, exercise, and smoking cessation.
Update medication profile. Include nonprescription medications, nutritional
supplements, and alternative medicines. Review for drug–drug and drug–disease
interactions.
Review and reinforce ADA Standards of Care, including the following:
o A1c quarterly for patients poorly controlled; semiannually for stabilized
patients. Review target values.
o Annual lipid panel
o Annual evaluation for microalbuminuria
o Annual retinal examination by an ophthalmologist (Note: less frequent
o
o
exams, every 2–3 years, may be considered in patients with a normal eye
exam.)
Annual foot examinations (Note: Patients with history of previous lower
extremity event should have monthly foot examinations.)
Blood pressure measurements every visit.
Sulfonylureas






First Generation: Tolbutamide (Orinase), Chlorpropamide (Diabinese), Tolazamide
(Tolinase), Acetohexamide (Dymelor)
Second Generation: Glipizide (Glucotrol), Glyburide (Micronase, Glynase,
DiaBeta), Glimepiride (Amaryl)
This drug stimulates the release of insulin from the pancreas. The pancreas may not
release insulin as rapidly as it should after one has eaten. The amount of insulin it
releases may not be sufficient to lower blood glucose concentrations.
Meals should not be skipped.
Symptoms of hypoglycemia must be watched for.
Weight gain is possible.
Repaglinide (Prandin), Nateglinide (Starlix)





This drug stimulates the release of insulin from the pancreas. The pancreas may not
release insulin as rapidly as it should after one has eaten. The amount of insulin it
releases may not be sufficient to lower blood glucose concentrations.
Dose should be taken up to 30 minutes before meals.
Drug should not be taken if meal has been skipped.
Symptoms of hypoglycemia must be watched for.
Weight gain is possible.
Metformin (Glucophage)


This drug decreases the production of glucose by the liver. The liver is probably
producing more glucose than normal and this is contributing to high blood glucose
levels.
Initially, gastrointestinal discomfort or diarrhea may be experienced. This usually
lessens with time and can be minimized if taken with food and if doses are gradually
increased.


Any change in general health should be brought to the attention of the clinician in
charge of the patient's diabetes management. This applies particularly to problems
affecting the heart, lungs, kidneys, or liver. Unusual symptoms to be reported to the
clinician include the following: severe fatigue, unexpected stomach discomfort,
dizziness, shortness of breath, unexpected fluid retention, or sudden development of
a slow or irregular heartbeat.
The drug may have to be discontinued temporarily if a special x-ray examination or
radiologic procedure is needed. Under these circumstances, the radiologist or
general physician must be reminded that metformin is being taken.
Thiazolidinediones (Rosiglitazone [Avandia], Pioglitazone [Actos])






These drugs improve the ability of the muscle to respond to insulin. Insulin allows
the muscle to take in glucose from meals and store it for future use.
Drug should be taken once daily or twice daily with or without food.
Rarely, rosiglitazone has been associated with liver problems. Blood tests should be
checked for liver function every 2 months as directed by the clinician. Any unusual
symptoms of fatigue, gastrointestinal distress, or increased abdominal girth should
be reported to the clinician.
Menstrual periods may resume and pregnancy may occur. (For patients with
polycystic ovarian syndrome only.)
A birth control pill with higher amounts of estrogen may be required. A physician
should be consulted. (For patients taking low-dose oral contraceptives.)
Any reappearance of menopausal symptoms, such as hot flushes, should be reported
to the doctor. (For patients taking estrogen replacement therapy.)
α-Glucosidase Inhibitors (Acarbose [Precose], Miglitol [Glyset])




These drugs slow the absorption of sugars and starches from the intestines. They do
so by blocking the breakdown of these foods.
Each dose should be taken with the first bite of each meal.
When these drugs are begun, gas and soft stools or diarrhea may be experienced.
This lessens with time and can be minimized by increasing the dose gradually as
prescribed.
Acarbose or miglitol by themselves do not cause hypoglycemia, but low blood
glucose levels can occur if they are used in combination with other antidiabetic
agents. Commercially available glucose tablets should be used to treat low blood
sugar reactions because other carbohydrate sources, such as those containing
sucrose or fructose, may not be absorbed quickly if acarbose or miglitol is being
taken.
Insulin




This drug is used to supplement the insulin secreted by the pancreas.
Rapid- and short-acting insulins are designed to help cells utilize glucose from
meals about to be eaten. Insulin lispro or insulin aspart should be given 15 minutes
before a meal. Eating should not be delayed. Regular insulin generally is given 30
minutes before the meal.
NPH (or Lente) insulin can last for 12–24 hours depending on the dose being used.
This insulin is primarily used to maintain low levels of insulin between meals. This
insulin decreases glucose production by the liver.
Insulin glargine is used as a basal insulin. It cannot be mixed with other insulins in
the same syringe.
FIGURE 50-9 A stepped-care approach to
treating type 2 diabetes mellitus. See Question 49
for discussion.
View Figure
I n su mm a r y, i f t wo o r a l ag e n ts i n c om bi n at i on do n o t wo r k , o ne c o ul d t r y a d i ff e r en t
c om b in a ti o n o r t r ip l e o r al t he r a p y. H o we ve r , i t is l i ke l y th a t a be d ti me do se o f i ns ul i n i n
c om b in a ti o n wi t h th e o r al a ge n ts (e . g. , a su l fo n ylu r e a , me t fo r mi n , o r TZ D ) wi l l b e n ee d ed . Th e
c om b in e d us e o f i n su li n p l us o ra l t h er a p y wa s o nc e c on si d e re d a b ri dg e to i ns ul in
m o no t he r ap y. H o we ve r , a su bs t u d y o f th e U K P DS d em o ns t ra t ed th a t t h e e a r l y ad di t io n o f
i n su li n to pa t ie n ts wi t h in a d eq ua t e r e sp on se s t o o r a l s ul f on yl u re as ( F P G > 1 0 8 ) im p ro ve d
g l yc em ic c o nt r ol o ve r i nsu l in t he r ap y a lo n e o ve r an a ve r ag e f o ll o w - u p p e r io d of 6 yea r s.
F u r t he r mo r e, t he g ro up o n c om b in e d t he r a p y s uff e r e d 5 0% m o re e pi so des o f ma j or
h yp o g l yc em i a; we i g ht gai n wa s c om p ar a bl e . 1 9 1 If t hi s f a il s, t he pa t ie n t is t r e at e d wi t h in s ul in
m o no t he r ap y. F o r p at i ent s wh o a re ga in i ng we i g ht b ec au s e t he y r e qu i re lar g e i n su li n d os es ,
TZ D s o r m e t fo rm i n ca n be a dd e d t o ac h ie ve co n tro l wi t h l o we r d os es i n i ns u li n .
Typ e 2 d ia b et es is a p r og r e ss i ve co n di t io n , wh i ch is hi g hl y l ik el y t o r e qu ir e d ru g th e ra p y. In th e
U K P D S , o nl y 1 6% a n d 19 % of t he s u bj ec ts ac hi eve d a n F P G < 10 8 a nd A 1 C < 7 %, r es pe c ti ve l y,
a f t e r 3 yea r s o f d i et a r y th e r ap y. 1 92 B y 9 yea r s , o n l y 9% we r e ab le t o mai n t ai n t h ei r g l yc emi c
g o al s u si n g d ie t t h e ra p y a l on e . 1 9 2 W e h a ve d e vel o pe d a si mp le al g o ri t hm t o ai d t h e cl in ic i an
i n s e le ct i ng d ru g t h er a p y f o r a pa t ie n t wi t h t yp e 2 d i ab e te s wh o h as no t ad e q ua t el y r es p on de d
t o li f es t yl e in t e r ven t io ns ( F i g . 5 0 -1 0 ). A lt h ou g h t he U K P D S de mo ns t r a te d th a t th e
s u lf o n ylu r ea s , me t f or mi n, a nd in su l in r ed uc e g lu co s e wi t h e qu al ef f ec t i vene ss ( TZ D s we r e n o t
s t ud i ed ) , 22 , 19 3 i mp o r ta nt f ac t o rs c om e i n to pl a y wh e n s el ec t in g a d ru g f or a pa t ie n t. Th e
a l go r i th m is b as ed on the p at i en t ' s u nd e rl yi n g p at h o ge n es is , d eg r e e o f cur r e n t g l yce mi c
c o nt r o l, an d p r e -e xi s t i ng c on d it i on s t ha t c o ul d p re d is p os e t he pa t ie n t t o ad ve r s e e f fe ct s o f a
d r u g . Th e pa t ho g en ic fea t u r es a r e d e du ce d f r om t h e p a ti en t ' s b od y we i g ht . I f t h e p at i en t i s
o b es e , i t i s p re s um ed the r e i s a n e l em en t o f i ns ul i n r es is t a nc e a nd in cr e as e d h ep a ti c g lu co se
o u t pu t . I f th e p a ti en t is le a n , h e o r s he is pr e s u me d to be in su l in de f ic ie n t.
I n t he c as e o f in su li n re si s ta nc e i n a n o b es e p a tie n t , f o r e xa m p le , m e t fo rm i n, wh i ch de c re as e s
h e p at ic gl uc os e o u tp u t an d in su li n re si s ta nc e ( i nd i r ec tl y) wi t h o u t ca us i ng we i g h t g a in m i gh t b e
p r e f er r e d i f t he r e a r e n o c o nt r a in di ca t io ns t o i ts us e . On e m us t a l wa ys ke ep i n mi n d t ha t th e
p r i ma r y go a l is t o n or m ali ze g lu co se co nc en t r at i on s , b ec a us e h yp e rg l ycem i a h as b e en m o st
c l os el y co r r el a t ed to th e d e ve l op me n t o f l on g - te rm co mp li ca t io ns . Th us , ag e n ts th a t ma y c au se
we i g h t ga i n ( e .g . , s ul f onyl u r e as ) a r e s t il l ve r y e f fe c ti ve .
A n o t he r fe a tu r e t h at de te r m in es c h oi ce of ag e nt i s th e d eg r e e o f c ur r e nt c o nt r o l. I f, fo r
e xa m p l e , t he pa t ie n t 's A 1 C va l ue is 2% to 3% hi gh e r th a n t he ta r g et le ve l , i t wi l l n ot ma ke
s e ns e t o u se an ag e nt t ha t on l y mo de s tl y l o we r s th i s l e vel . F i na ll y, i t i s imp o r t an t t o e va l ua t e
t h e p a ti e nt ' s re n al , l i ve r , c a rd i o vasc u la r , a n d G I fu n ct i on be f o re pr e sc ri b ing a s pe ci f ic ag en t ,
b e ca us e th es e c on di t io ns co ul d p r e di sp os e t h e pa t i en t t o ad ve r se ef f ec ts . Ta b l e 5 0 - 29
c om p a re s a nd c o n tr as t s t h e e f fi c ac y, ad va n ta ge s, a nd di sa d va nt a ge s o f an t i di ab e ti c a ge n ts
u s ed to t re a t t yp e 2 di a be t ic pa t ie n ts an d c an be u s ed in c o nj u nc ti o n wi t h t h e b as ic al g o ri t hm
t o se le c t d ru g s f o r a s pec i fi c p a ti en t . Ta bl e 5 0 -3 2 s um ma r i zes t re a tm en t of t yp e 2 di a be t es
u n d er sp ec ia l c i rc um st a nc es .
S e ve r a l n e w c om bi n at io n p r o du ct s t h at c o mb in e t wo o r a l ag en t s i nt o o n e m e di ca t io n a r e
a va i la b le (s e e Ta b l e 5 0 -2 9 ) . Al t ho ug h th es e p r odu c ts a re ap p ro ve d a s f i rst - l in e th e ra p y ( th u s
s ki p pi n g t he m o no t he r a py s t e p ), we r ec om me n d th a t th e y be r es er ve d fo r u s e i n p at i en ts
wh o s e me di ca t io n re g ime n s mu s t b e si mp l if i ed to e n ha nc e a d he r en ce .
Clinical Use of Oral Agents
Selecting an Oral Agent
W h i c h o f th e o r a l a g en ts w o u l d yo u r e c o m me nd f o r L. H . a t t h is t im e ?
L . H . is a t yp ic al o ver we i g h t t ype 2 p at i en t wi t h ea r l y e vi de nc e o f c a rd i o va sc u la r di se as e (m il d
h yp e r t en si on ) , bu t wi t h no e vi de nc e o f m ic r o vas cu l a r c om pl ic a ti on s . H e r l ive r , r e na l , a nd G I
f u nc t io ns a re no r ma l . F ina l l y, s he ha s a ch ie ve d im p r o ved c o nt r o l wi t h di et a nd e xe r c is e a s
e vi d e nc ed b y a n i mp r o ved A 1 C , F P G , an d t r i gl yc e ri d e c on ce n t ra t io n . H o we ve r , h e r p os tp r a nd ia l
g l uc os e a n d A 1 C val u es c o nt i nu e t o e xc e e d ta r get l e vel s ( < 18 0 m g /d L a nd < 7 %, r es pe c ti ve l y) .
P a t i en ts li ke L. H . wi t h mo d e ra t e t o s e ve re t yp e 2 d i ab e te s h a ve va r yi n g de g r ee s o f β -c el l
d ys f un c ti o n a nd ti ss ue re s is ta nc e to in su li n . I n th e se in di vi d ua ls , pu ls a ti le i ns ul in se c re t io n
a n d f i rs t - ph as e i ns ul i n r el e as e a r e a bs e nt , a n d t he p an c re as is “b li n d ” o r u n r es po n si ve to hi g h
g l uc os e c on ce n t ra t io ns (g l uc o to xi c i t y) . Be ca u se ta r g e t t iss u es ar e l es s res p on si ve t o in s ul in ,
h e p at ic gl uc os e o u tp u t typ i c al l y is i nc r e as ed an d p a ti e nt s m a y re q ui r e h igh e r c o nc en t r at i on s o f
i n su li n to ac hi e ve t h e sam e d e g re e o f p e ri p he r al g l uc os e u t il i za ti on o bs erve d i n p eo p le wi t h ou t
d i ab e te s m el li t us . At t hi s s t ag e , a ll c l ass es o f o ral a nt i di ab e ti c a ge n ts an d i ns u li n a r e l ik el y t o
wo r k e q ua ll y we l l , al t ho ug h in su li n c a us es m o re we i g h t ga i n a nd h ypo gl yc em i a t ha n th e o r al
a g e nt s. 2 2 , 1 93 Th e r ef o r e, t h e mo d e o f t he r a p y s ele c te d d e pe n ds o n p a ti e nt a nd p re sc r ib e r
p r e f er e nc e .
FIGURE 50-10 Suggested treatment algorithm for type 2
diabetes. FBG, fasting blood glucose; FPG, fasting plasma
glucose; SFUs, sulfonylureas; TZD, thiazolidinedione.
View Figure
P . 5 0 -6 2
P . 5 0 -6 3
B e c au se L. H . is o ve r we i g h t , t h e a lg o ri t hm s ug g es t s t he us e o f a g en ts t hat l o we r th e b l oo d
g l uc os e wi t ho u t c au si ng we i g h t ga i n. Th u s , ac a rbo s e a nd m e t fo r mi n a r e fa vo r e d . A TZ D ma y
a l so be c o ns id e r ed e ven t h ou g h i t c an c a us e we i g h t g a in , s in ce t he pa t ter n o f we i g h t g ai n
i n du c ed b y t h is a g en t ( red u ct i on in vis ce r a l a di pos e ti ss ue ) i s m et a bo li c al ly b e n ef ic i al .
O f t e n , a ca r bo se is el im ina t e d f r om c o ns id e ra t io n b e ca us e s lo w t i t r a ti on is r e q ui r e d t o mi n im i ze
G I e f f ec ts ; a n ec do t al l y, h o we ve r , p eo p le of Me xi c a n - Am er ic a n o r ig in , s uch as L . H. , s e em l es s
s us c ep ti b le to f la t ul en ce a n d d ia r r he a . A ls o , b eca u se ac a rb os e h as le ss d r a ma t ic e f fe c ts o n
t h e FP G ( 2 0 t o 3 0 m g/ d L d ec r e as e ) a nd A 1 C ( 0 .5% t o 1 . 0% de cr e as e ) t han t he o th e r a ge n ts ,
b i oc h em ic al go al s a r e l es s l ik el y t o b e a ch i e ved in p at i en ts wh o s e A 1 C i s ≥ 8 . 5 %. H o we ve r ,
a c a rb os e c an be co ns id er e d i n L. H . b e ca us e h e r p o o r c on t r ol i s c ha r ac t e ri ze d b y p o st p ra n di al
h yp e r gl yc em i a as we l l as an F P G an d A 1 C th a t a re n ea r in g th e g oa ls es t ab l is he d fo r he r .
Me t f o r mi n is f a vo re d a s a f i rs t -c ho ic e a g en t fo r ob e se , t ype 2 d ia b et ic pa ti e n ts b y m an y
e n d oc ri n ol o gi st s b ec au se i t is as ef f ec t i ve as t he s ul f on yl u r ea s b ut do es n o t c au s e
h yp o g l yc em i a o r we i gh t g a in ( se e Ta bl e 5 0 -3 0 ) . H o we ve r , m ul t ip l e d ai l y d o si n g is r eq ui r e d
i n i ti al l y, a n d i ts do se al so mu s t b e t it r a te d to m i ni m i ze G I e ff ec t s. A ft e r the d os e is
e s ta b li sh e d, it is po ss ib le t o u se a l on g -a c ti ng p ro d uc t th a t ca n b e d os e d o n ce da il y. R e na l
f u nc t io n te st s s ho ul d b e e va l u at e d b ef o re t he d rug is in i ti a te d . L . H . d oe s n o t h a ve a n y
c o nt r a in di ca t io ns ( r en al , l i ve r , h e pa ti c d ys f un ct i on , bi n ge al co h ol us e) t o th e us e o f m et f o rm in
t h a t c ou ld p re d is po se her t o i t s mo s t si g ni fi ca n t si d e e f fe c t, la ct ic ac id o si s ( s ee Q u es ti o n 6 6 ).
R o s ig l it a zo n e o r pi o gl i tazo n e a l s o ca n b e u se d as mo no t he r a p y a n d, li ke m e t fo rm i n, ne i th e r i s
l i ke l y to ca us e h yp o gl yce m ia , b u t we ig h t g ai n i s p o ss ib l e. Th e i r e ff ec t s on F P G an d A 1 C a re
i n t er m ed ia t e b e t we e n t ho s e o f a ca r bo se an d m e tf o r mi n o r th e s ul f on yl u r ea s , s o t ha t i t is l ik e l y
t h a t t h e g oa ls es ta b li sh ed f o r L . H . co u ld be ac hi eve d wi t h ei t he r ag e nt as m o no t he r ap y. S i de
e f f ec ts a re r ar e , a nd b oth ca n b e g i ve n a s a s in gl e da il y d os e , wh i c h is ap p e al in g f o r p a ti e nt s
o n m u lt i pl e -d r ug t he r ap y. L F Ts m us t b e e va l ua t ed a t b as el i ne an d b im o nth l y t he r e af t e r f o r t he
f i r st ye a r o f t h e ra p y fo r ro s ig li t a zon e or pi o gl i ta zo n e , wh i c h c an be di f fi cul t fo r pa t ie n ts to
a d h er e to an d a dd s t o the co s t o f t h er a p y. Th e TZ D s r em ai n t h e mo st e xp e n si ve of t he
a n t id ia b et ic ag e n ts . 1 9 0
F i n al l y, o n e sh o ul d n o t fo r g e t t ha t u n ti l th e n e we r a g en ts be ca me a vai l abl e , s ul f on yl u r ea s we r e
u s ed qu i te s u cc ess f ul l y to t r ea t o b es e p a ti en t s wi t h t yp e 2 d i ab e te s. Th e se a ge n ts a r e
r e l at i ve l y t ro ub l e f r ee wi th r e ga r d t o s id e e f fe c ts (we i g h t ga i n a nd occ as i on a l h yp o gl yc em ia ) ,
a n d m an y c an be do se d o n ce da il y. Th e y a r e very e f f ec t i ve a nd m a n y a re n o w a va i la b le in
g e n er ic f or m , ma ki n g t hem qu i te a ff o rd a bl e wh e n c os t is a p ri ma r y co ns i der a t io n (s ee Ta b le
5 0 - 30 ) .
B a s ed on th is di sc us si o n, we f a vo r th e u s e o f me tf o r mi n (s ee Q u es ti o n 5 2 ) o r ac a rb os e i n L . H .
Acarbose
I f a ca r b o se is us e d , h ow sh o u ld i t b e p r e sc r i be d ? H ow s h o ul d L . H . be c ou n se l e d a nd
m o n i to r e d ?
A c a r bo se s h ou ld b e t ak en wi t h ea c h me a l t o d el ay a n d s lo w t h e ab so r p ti on o f c om pl e x
c a r bo h yd ra t es . Ho we ve r , b ec a us e m an y p at i en ts e xp e r i e nc e b o t he rs om e fl a t ul en ce , bl oa t in g ,
d i a r rh e a, an d a b do mi na l p a in in i ti a ll y, on e s ho u ld b e gi n wi t h 2 5 mg t h re e ti m es d a il y a nd th e n
t i t r at e u p wa r d b y d o ub l ing t he do se e ve r y 4 t o 8 we e k s . Th is ti t ra t io n m ini m i zes G I e f fe c ts ,
wh i c h di ss ip a te wi t h ti me. A l te r n at i ve l y, a do se of 2 5 m g o nc e a da y ( wi t h a n e ven i ng m e al
o ve r t he we e k en d wh e n u n e xp e c te d e f f ec ts ar e le a st li ke l y t o i nt e r fe r e wi t h a wo r k sc he d ul e )
c a n b e i ni t ia t ed . As on e c a n se e , i t c ou l d t ak e a pp r o xi m a t el y 3 t o 4 mo n ths t o t it r a te L. H . to
t h e m a xi m um do se . Th us, s he s h ou ld be a d van ced as qu ic kl y a s p os si bl e b a se d o n h e r
t o l er a nc e t o t h e G I e ff ect s , b ec a us e so m e in d i vidu a ls to l e ra t e t he d ru g q ui t e we l l.
L . H . s h ou l d b e in s t ru ct ed t o t ak e a ca r b os e wi t h th e fi r st bi t e o f e ac h m ea l, b ec au s e i ts
m ec h an is m o f a ct i on is to d el a y th e a bs o r pt i on of c a rb o h yd ra t es . Th e n atu r e of ac a rb os e ' s G I
s i de ef f ec ts sh ou l d b e e xp l ai n ed in th e c o nt e xt o f t e ac h in g h e r h o w t o g r a du a ll y i nc r ea se he r
d o se . Sh e s ho u ld c o n ti nu e to pe r f o rm S MB G a s d e sc r ib ed in Q u es ti o n 4 8 b ec a us e h e r f in a l
d o se wi l l b e d e te r mi ne d b y h e r g l yce mi c c on t r ol a s we l l as t he hi gh e st dos e s he is ab le t o
t o l er a t e. S he s h ou l d al so b e a d vis ed to a vo id pro d uc ts su ch as Be a no , wh i ch a re de si gn e d t o
m i ni mi ze fl a tu l en ce , b eca u se th e y co n ta i n ca r b oh yd r a t e - s pl it t in g e n zym es an d m a y de c re as e
t h e e f f ec ti ve n ess o f t he d r u g .
Metformin
N . H . i s a 46 - ye a r - o l d , ob e s e ( B M I 2 8 k g/ m 2 ) m an w it h a h is t o r y o f h yp e r t e n si o n , p e r ip h e ra l
va s c u l a r d i se a se , re c u rr e n t de e p ve no u s t h r om b o si s , a n d h yp e r l i p i de m i a. H e p r e se n t s
w i t h c om p la i n t s o f fa t ig u e a n d n o c tu r i a . N . H . h a s s m ok e d 2 pa ck s o f c i g a re t t e s/ d a y f o r 1 5
ye a r s a n d h as a s t r on g f a m i l y h i s t o r y o f C H D . A r a n d o m p la s ma gl u cos e >2 0 0 m g/ d L o n
tw o o c ca s io n s ( 2 48 an d 2 0 7 m g /d L ) a n F P G o f 1 5 0 m g /d L ( no r m al , <1 26 m g/ d L ) a n d a n A 1 C
o f 9 .2 % ( n o r m a l , 4 % t o 6 %) a n F P G o f 15 0 m g /d L c on f i r ms t he d ia g nos i s of t yp e 2
d i a be t e s. C u r r e nt me d ic a t i on s in c lu d e e na l a p ri l a nd l o va st a t in a nd t es t s o f l i ve r an d
r e n a l fu n c ti o n a r e w i th in n o r ma l li m i ts . A 1 - mon t h t r i al o f d i et a nd ex er c i s e h a s l i t tl e
e f f e c t o n N. H . ' s g l uc o se c on c en t r a t io n s . W h y w o ul d me t f o rm i n o r a TZ D b e th e i n i t ia l
d r u g s o f ch o i ce f o r N . H. ?
W e wou l d n ot se le c t su l fo n yl u re as o r i ns ul i n as in i t ia l d r ug s o f c ho ic e f o r N . H . be c au se th e y do
n o t e xe r t a f a vo ra bl e e f fe c t o n p la sm a l ip i ds a n d g e n er a ll y a r e as so ci a te d wi t h we i g h t g ai n . W e
a ck n o wl e dg e t h at so me s u lf o n ylu r ea s re ma in t he l e as t e xp e n si ve o ra l a n ti d ia b et ic ag e nt s , a nd
t h is ma y b e a n im p o rt a nt f a ct o r i n t h e i ni ti a l se l ect i o n o f t h er a p y fo r s om e p a t ie n ts . A l th o ug h
s u lf o n ylu r ea s o r i n su li n d e c re as e b lo o d g lu co se c o nc en t r at i on s i n p at i en ts li ke N . H . , t he y d o s o
b y i nc r e as in g i ns ul i n co nc e nt r a ti o ns . P a ti e nt s s uch as N . H . a r e l ik el y t o h ave β - c el l
d ys f un c ti o n, as e vi d en ced b y po o r f i rs t - ph as e i nsu l in r el e as e; ho we ve r , i n t h e e a rl y s ta g es o f
t yp e 2 d ia b et es , th e y al so a r e li k el y t o e xh i b i t h igh i ns ul in co nc e nt r a ti on s , wh i c h s u gg es ts
r e s is ta nc e o f pe r ip h er a l t i ss ue s t o i ns u li n a ct i on . Th i s c a n b e o ve rc om e by i n c re as i ng in su li n
l e ve ls , b u t h yp e ri ns u li nem i a p r om ot es f ue l s to r age a nd of t en is a cc om p ani e d b y h un g er ,
o cc a si on a l h yp og l yce mi a, a nd we i g ht ga i n. I nt e r es t in g l y, r es e a rc h su g ge st s th a t t he
s u lf o n ylu r ea s m a y c lo s e A TP - s e n si t i ve p ot as si um c ha n ne ls in c a r di ac ti ssu e , s im il a r t o th ei r
a c ti o n a t t h e β - ce ll . In t he h ea r t , t hi s e f fe c t co u ld l im i t ci r cu l at i on to an isc h em ic a r e a. 1 28 , 17 8
Th e a va i la bi l it y o f a n ti h yp e r gl yc em ic ag e nt s s uc h a s a ca r bo se , m e t fo rm i n, a n d TZ D s p ro vi d es
a l t er n a ti ve s f o r p at i en ts l i ke N . H ., wh o p oss es s th e c h a ra ct e r is ti cs o f th e i n su li n re si s ta nc e o r
m e ta b ol ic s yn d r om e ( se e P a t ho g en es is ) .
I n li g ht of N . H . ' s A 1 C valu e ( 9. 2 %) , ac a rb os e a s m o no t he r ap y wo u l d no t b e s u f fi ci en t to at t ai n
n e a r -n o rm al pl as ma gl u co s e
P . 5 0 -6 4
c o nc en t r at i on s. R os i gl it azo n e o r p io gl i ta zo n e im pr o ve p er i ph e ra l ta r ge t ti ss u e r es p on se s t o
i n su li n a n d l ip id p ro f il es . H o we ve r , t h e y a r e c on sid e r ab l y mo r e e xp e n si ve t h a n me t f or mi n ,
wh i c h is a va i la b le ge ne r ic a ll y, an d th ei r ef f ic ac y a s m on o th e r ap y is so mew h a t l es s . H o we ve r ,
N . H . is t ak in g s e ve ra l o th e r m e di ca t io ns an d m a y p r e fe r th e c on ve n ie nc e o f a s in gl e - da il y - d os e
t h e r ap y.
Me t f o r m i n a pp e ar s t o l owe r b l o od gl uc o se c o nc en t r a ti o ns b y d ec r ea si n g h e p at ic gl uc os e
p r o du c ti on . It al so h as be n e fi ci al e ff ec t s o n p la sm a l i pi d c on ce n t ra t io ns a n d p r om o te s we i g h t
l o ss o r at le as t p re ve n ts we i g h t ga i n. N . H . h as no r i sk fa ct o rs fo r la c ti c ac id o si s ( e .g . , re na l ,
l i ve r , o r c a rd i o re sp i ra t o ry d i se as e ) th a t wo u l d b e c on t r ai n di ca t io ns fo r th e u se o f me t f or mi n .
B e c au se N . H . e xh i b i ts the t yp ic al f ea t ur e s o f i ns ul i n r es is t a nc e s ynd r om e a n d h as no
c o nt r a in di ca t io ns f or i ts u s e, me t fo r mi n wo u ld be t h e i ni t ia l d r ug o f ch o ic e.
Titrating Metformin Doses
N . H . i s s t a r te d on me t fo r m i n 5 0 0 m g B I D w i t h f o o d a n d i n s t r uc t ed t o in c r e as e h i s d o sa g e
t o 5 00 mg T I D a f t e r 1 w e e k . Tw o da ys l a t e r , he p h o ne s th e c l i ni c c o mp l a i ni n g o f na u se a
a n d di a r r h ea . He a dm i ts t o ta k in g hi s do s es on a n e m pt y s t o m a c h. How s h o ul d N . H .' s
s ym p t o m s b e a dd r e ss ed ?
G I d is t u rb a nc es s uc h a s d i a r rh e a, bl o at in g , a n or exi a , a b d o m in al di sc om f o rt , n au se a , a nd
m e ta l li c t as t e o ft e n d iss ip a t e wi t h t im e a nd c a n be mi n im i zed b y i n it i at i ng m e t fo rm i n i n a
s i ng le , 50 0 - o r 8 5 0 -m g do s e a t b r ea k fa st o r wi t h th e pa t ie n t 's la r ge s t me a l o f th e d a y. Th e
d o sa g e sh o ul d b e s lo w ly i nc r e as ed ( e. g ., 50 0 m g/ d a y e ve r y 2 we e k s) un t il t h e a pp r o pr i at e
c l in ic al e ff ec t i s a ch i e ved o r t h e p at i en t i s t ak i ng t h e m a xi m um d os e (1 , 00 0 m g t wi ce da il y o r
8 5 0 m g t h re e t im e s a d ay) . Th e r e f o re , N . H. ' s m e tf o r mi n d os e s ho u ld be r ed u ce d t o 5 0 0 m g
d a il y wi t h a m ea l , a nd he s ho u ld be ti t r at e d mo r e s l o wl y o ve r a pe r i od of se ve r a l we ek s t o 5 0 0
m g th r ee ti me s a da y o r h i gh e r a s t o le r at e d. Me t f o r m in i s t yp ic a ll y d os ed two t o t h r ee ti me s
d a il y ( t h e lo n g -a ct i ng fo rm u la t io n i s d os ed on ce da i l y wi t h d i nn e r ).
Monitoring Metformin Thera py
H ow s h o ul d me t f o rm i n t h e r a p y b e m o n i t o re d in N . H . ?
A s is s t an d ar d wi t h o t he r a g en ts , N . H . sh o ul d b e e n co u ra g ed t o p er f o rm SMB G a n d ha ve an
A 1 C t es t p e r fo r me d q u ar te r l y u nt il he ac h ie ve s con s is te n t val ue s o f < 7 % . A d d i ti on a l e vi de nc e o f
m e t fo rm i n 's th e r ap e ut ic b e n ef i ts m a y in cl ud e a n im p r o ved li pi d p r o fi le an d s om e we i gh t l os s.
I n i ti a ll y, it is i mp o r ta n t to f ol l o w G I p ro b le ms a n d, a lt h ou g h l ac ti c a ci do si s i s u nl ik e l y, N. H .
s h ou l d b e wa r n e d t o b r ing t o t h e a tt e nt i on of hi s p h ys ic ia n a n y su dd e n s ym p to ms of sh o rt n es s
o f b re a th , we a kn es s, and ma l ai se . A b as el i ne S rC r , L F Ts , a nd C B C s h ou ld b e o bt a in e d f o r
N . H . a nd r ep e at e d ye a rly.
Sulfonylureas
Af t e r 3 w ee k s, N . H . r e tu r n s t o t h e c l in i c c om pl a i n in g vi g o r ou s l y a b o u t u n r el e n ti n g
“ s t om a ch pa i n” an d di ar r h e a . He c on t i nu e s t o t a k e m e t fo r m i n 5 00 mg B I D w i th f oo d an d
h a s e ve n t r i ed an t a ci d s, w hi c h f a il t o re l ie ve th e pa i n . H i s b l o od g lu co s e re c o r ds su g g es t
t h a t t he me t f o rm i n i s be g i n ni n g t o w o r k w e l l ( fa s t i ng , 13 0 t o 16 0 m g /dL ; p r e - l u n ch an d
p r e - d i nn e r , 1 50 t o 1 8 0 m g / d L) , bu t N . H . w an t s t o sw i t ch t o a n ot h e r a ge n t — p r e fe r a bl y
s o m e th i ng t ha t ca n be t a k e n o nc e d a i l y. R o s i g l i t az o n e i s s u gg e st e d , b u t N . H . 's he a l th
i n s u r an c e d oe s no t in c lu d e d ru g be n e fi t s a n d it w ou l d b e p r o h i bi t i ve ly e x p e n s i ve .
E ve r yo n e a g r e es t ha t th e su l f o n yl u r e a s s h ou ld b e t ri e d. W hi c h a g en ts c ou l d b e us e d?
H ow s h o ul d t he y b e d os e d ?
P a t i en ts wh o a re mo st lik e l y to re s po nd f a vo ra bly t o o ra l s ul f on yl u r ea s i nc l ud e t h os e wh o a r e
o l de r t ha n 4 0 yea r s o f ag e , h a ve b e en di a gn os ed wi t h i n t he la s t 5 yea r s, a r e wi t hi n 1 1 0% to
1 6 0 % o f I BW , a nd ha ve a n F P G o f <2 00 mg / dL . If p a ti en t s h a ve b ee n t r ea t e d wi t h in su l in ,
t h os e wh o se r eq ui r em e nt s ar e <4 0 U/ d a y (i n di ca ti n g e nd o ge n ou s p an c re at i c r es e r ve ) a r e m os t
l i ke l y to r es po n d. 1 45 , 146 N . H . fu l fi ll s t he s e c ri t er i a a n d d oe s n o t h a ve a ny c o n t ra in d ic at i on s t o
s u lf o n ylu r ea us e (s ee O ra l A nt i di ab e ti c A g en t s) . A p p r o xi m a te l y t wo - t hi r ds t o th r ee - f ou r t hs o f
t h e p a ti e nt s wh o m ee t a ll o f t he p re vi o us l y s p ec ifi e d c ri t e ri a wi l l ac h ie ve sa t is f ac t or y c on t r ol
i n i ti al l y. Th e re ma in d e r (1 6 % t o 3 6 % ) f ai l t o re spo n d t o a 1 -m on t h t r ia l o f m a xi m um t he r ap e ut ic
d o se s a nd a re c o ns id e r ed p ri m ar y f a il u re s. 1 45 , 146
Th e r e is li t tl e e vi d en ce th a t a n y pa r t ic ul a r o r al su l f on yl u re a i s m or e e f f ect i ve t ha n a no t he r in
p r o pe r l y s e le c te d p a ti en ts wi t h t ype 2 d ia b et es . Ho we ve r , a s p r e vio us l y dis cu ss e d, th e r e a r e
d i f fe r e nc es i n d u ra t io n of a ct i on an d s id e e f fe c ts t h a t s ho ul d b e c o ns id e red i n t he se le c ti on o f
t h es e a g en t s. ( S ee Ta ble s 5 0 - 29 an d 5 0 -3 0 a n d t h e s ec t io n o n O ra l An t idi a be t ic A ge n ts . )
W e r ec omm e nd ag a in st th e r ou t in e u se of ch lo r p ro p am i de an d a ce t oh e xa m i de be ca us e o f th ei r
s i de ef f ec ts an d a cc um u la t i on in pe op l e wi t h r en al d ys fu nc t io n . To l b ut am id e is a sa f e o pt i on in
p a t ie n ts wi t h r e na l d ys f un c ti o n si nc e i t is c on ve r te d to in ac t i ve m et a bo li t es ; a d is ad va n ta g e is
t h a t i s mu st b e d os ed t wo t o t h re e ti me s d ai l y. O f t h e f i rs t -g e ne r a ti on a gen t s , t ol a zam i de ha s
s e ve r al ad va n ta g es . I t ha s a n i n te r me d ia t e ac t i vit y s o t h a t co n t ro l u su al l y c an be ac hi e ve d wi t h
o n e d os e a n d, in so me ca s es , t wo d o se s p er d a y. H o we ve r , i ts du r a ti o n o f a c ti on is no t s o
p r o lo n ge d t h at ac cu mu l at i o n is li ke l y to r es ul t i n s e ve r e h yp og l yce mi c e pis o de s. H o we ve r , on e
s h ou l d b e ca u ti o us o f i t s u se in pa t ie n ts wi t h Cl C r o f <3 0 m L/ mi n ut e , b ec au s e i ts m e ta b ol i te s
a r e m il d l y a c ti ve . 19 4
G l i me p i ri de , gl ip i zi de , a nd g l ybu r id e a r e s ec on d - ge n e ra t io n a g en ts . G li p i zid e is m e ta bo l i zed to
i n ac t i ve p r od uc ts an d h as an in t e rm ed i at e d u ra t ion o f a ct i on . As wi t h t o la za m id e , ma n y
p a t ie n ts c an be co n t ro ll ed o n si n gl e d ai l y d os es , b u t t wi ce - da i l y d os es a re r e co mm en d ed fo r
p a t ie n ts wh o re q ui r e > 1 5 m g . B ec a us e g l ybu r id e h a s a l o ng e r d u ra t io n o f a c ti o n, it is
a ss o ci at e d m or e fr e qu e nt l y wi t h se ve r e , p r ol on g ed h yp og l yce mi a th an is gl i pi zi d e. F or t hi s
r e a so n , i t sh o ul d b e u sed ca u ti o us l y i n fr a il , e l der l y i nd i vi du a ls o r in th ose wh o , f o r a n y
r e a so n , a r e p re d is po se d t o h ypo g l yce mi a ( se e Q ue s ti o ns 6 9 a n d 7 4 ). G l ime p i ri d e ca n b e d os e d
o n ce da il y a n d ma y b e as so ci a te d wi t h a s l ig h tl y l o we r i nc id e nc e o f h yp o gl yc em i a t ha n
g l yb u ri d e.
F o r N . H ., t ol a zam id e , g lim e pi r id e , g li pi zi d e , o r g lyb u r i de wo u l d b e t h e a ge n ts o f ch o ic e
b e ca us e th e y ar e re as o na b l y s a fe , c a n b e d os ed o n ce da il y, a nd a re r el at ive l y i n e xp e ns i ve . He
s h ou l d b e i ni ti a te d o n l ow d o s a ge s ( e . g. , 1 0 0 t o 2 5 0 g to l a zam id e ; 1 to 2 m g g l im ep i ri d e; 5 mg
g l ip i zi de ; o r 1. 2 5 t o 2 . 5 m g g l yb u ri de ) on ce da i l y. E ve r y 1 to 2 we e k s, t he d os a ge ca n b e
i n c re as ed un t il t he th e rap e u ti c g oa ls a re ac hi e ved o r m a xi m um do se s o f th e se ag e nt s h a ve
b e e n r ea ch e d ( se e Ta bl e 5 0 - 29 ) .
P . 5 0 -6 5
Th e m an u fa c tu r e rs o f to la za m id e , g li pi zi d e, an d gl yb u r id e re co mm en d t wi ce - d ai l y do si n g o f
t h es e a g en t s o nc e a s pec i fi e d d os e h as b e en e xc e e d ed ; wh e th e r t h is a c tua l l y is n ec es s ar y h as
n o t b e en do cu me n te d . Ma n y cl i ni ci an s re co mm end t ak in g th es e a g en ts 30 m in u te s b e fo r e
m e al s so t ha t th e o ns e t o f ac t io n m or e c lo s el y ma t ch es f oo d a bs o rp t io n 14 6 ; th is m a y be le ss
i m po r t an t i n p a ti en t s t ak in g th es e a g en t s ch r o ni ca l l y, p a r ti cu la r l y f or t he in t e rm e di a te - a n d
l o ng e r - ac ti n g a ge n ts . 1 5 4 , 1 9 5 I f G I i nt o le r an c e occ u rs , th es e a g en ts sh ou ld b e t ak en wi t h fo o d.
C l i ni c al N ot e : N . H . wa s su cc e ss fu ll y t r e at e d wi t h d i e t, e xe r c is e, a nd re l at ive l y l o w d o se s o f
g l yb u ri d e ( 5 m g d ai l y) . W ithi n 4 m o nt h s, hi s A 1 C d r o pp ed t o 7 .3 % a n d h is S MB G r e s u lt s r a ng e d
f r o m 1 20 to 16 0 m g /d L . B y d e c re as i ng di e ta r y f at a n d e xe r c is i ng m o r e r egu l a rl y, h e wa s ab l e t o
l o se 10 po u nd s. I t is li kel y t h a t t he m o de s t we i g ht l os s as we l l a s h is im pro ve d gl uc os e
c o nc en t r at i on s r e du ce d in s ul in r es is t an ce , th e re by i m p ro vi n g t is su e r es p on s i ven es s t o h is
e n d og en o us i ns u li n . N . H. e n ro ll e d i n a s mo ki n g ce ss a ti o n p r og r am , b u t h as be e n u na b le to qu i t
s mo ki n g c om pl e te l y (s ee C h a pt e r 8 5 , To ba cc o U se a nd D ep e nd e nc e) .
Secondary Failure to Oral Agents
Pathogenesis
Secondary Failure to Oral Sulfonylureas
Q . R . i s a 68 - ye a r - o l d , 5′1 ″ , 14 0 - lb ( BM I 26 . 4 k g/m 2 ) Ja p an e se w o ma n w i t h a n 8 - ye a r
h i s t o r y o f t yp e 2 d i a be te s t ha t ha s b e en t r ea t ed w it h di e t , e xe r c is e , an d a va r ie t y o f
“ p i ll s .” Ac c o r d in g t o c li n i c re c o r ds , s h e w a s m o d e ra t e l y c o n t r o l l e d (F P G , 1 30 t o 1 60
m g / d L ; A 1 C , 7 . 5 % t o 8 . 5%) f o r 5 ye a r s w it h a su c c es s io n of o r al s ul f on yl u r e a s — m o s t
r e c e n tl y, g l i p i zi d e . R e ce n t ch a r t no t es i nd i ca te t h a t Q . R . ' s c hi e f c o mp l a i n ts ha ve i nc l u de d
l o s s o f ap p e ti t e a n d f a ti g u e . S h e h as l os t 15 lb o ve r t h e p a s t ye a r , a nd h e r A 1 C h as be e n
i n c r ea s i ng a t e ac h vi s it ( f r o m 8 . 5 % 1 ye a r a g o t o 1 1 % c u r r e n t l y) . T h e d o s e o f gl i p iz i de
a l s o h a s b ee n in c r ea s ed f r o m 1 0 m g d a i l y 1 ye a r a g o t o 2 0 m g tw ic e da i l y f o r t h e pa s t 6
m o n t hs . O t he r me d i ca l p r o b l em s i n c lu d e h yp e r t e n s io n m a na g e d w i t h h yd r o c h l o r o t h i az i de
2 5 mg da i l y a n d m i l d pe r i p h e ra l ne u r o pa t h y m a n a ge d w i th n ap r o xe n 5 0 0 m g tw ic e d a i l y.
At t h i s c l in i c vi si t Q . R . , w ho i s w e l l k n ow n t o yo u , se em s pa r t i cu l a r l y l i s t le s s a n d f l at i n
h e r a f fe c t . H e r bl o o d g lu c o se r ec o r d s, w h i ch ar e t yp i c a l l y m e t i c u lo u s , a r e in c om p le t e .
B l o o d gl u co s e va l u es co n s is t e n tl y e x c e e d 2 00 m g / d L a nd r a ng e f r om 2 0 2 to 34 0 m g / dL .
W h i l e t a ki n g h e r h i s to r y, yo u d i s c o ve r t h a t h er h u s ba n d p a ss e d aw a y l a s t ye a r a n d t ha t
o n e of h e r a d ul t ch i l d ren h as r e ce n t l y b e e n d i ag n o se d w i t h a te r m in a l i l l n es s . W ha t
f a c t o r s m a y b e c o n t r i bu t i n g to Q . R . 's po o r g luc o s e c on t r o l ?
S e ve r a l f ac t o rs m a y be co n t ri b u ti ng t o Q . R . ' s d e te r i o ra t in g b lo o d g lu co se c o nt r o l a nd ap pa r e nt
l a ck o f re s po ns i ven e ss to t he o ra l s ul f on yl u re a s o ve r t h e pa s t ye a r (a s e vi d en c ed b y h e r
e l e va te d b l oo d g lu co se an d A 1 C , li s tl es sn es s, an d we i g h t l os s ) . S ec o nd a r y f a il u re t o t he
s u lf o n ylu r ea t he r ap y i s fa i r l y c om mo n a n d oc cu r s a t a r a te of ap p r o xi m at el y 5 % to 10 % p e r
ye a r i n p at i en ts wh o in i tia l l y ar e we l l c on t ro l le d on t he se ag e nt s , as wa s Q . R . 1 4 5 , 1 46
S e c on d ar y f a il u re is c ha ra c te r i ze d b y p ro g re ss i vel y p o o r g lu co se c o nt r o l th a t o cc u rs af t e r a 1 m o nt h to a se ve r a l - ye a r p e r io d o f go od r es po ns e . Th e c au se of se co n da r y f a il u re is un kn o wn ,
b u t i t m a y be r el a te d t o p r o g re ss i ve p an c re a ti c fa i lu r e ; p oo r c om p li a nc e wi t h d i et , e xe r ci s e, o r
m e di ca t io ns ; a n d e xo g e no u s d ia b et o ge n i c f ac t o rs s uc h a s o be si t y, il ln es s , o r d ru gs . ( Se e
Ta b l e 50 - 36 . D r ug - in d uce d h ype r gl yc em i a is ad dr e ss e d l at e r i n t h is c ha p te r . )
Th e U K P D S c on f ir me d tha t se co n da r y f ai lu r e re p re s en ts a n a tu r al p ro g re ss i on of t yp e 2
d i ab e te s . Th e in ve s ti ga to r s f o un d s ec on d a r y fa ilu r e occ u r re d a t th e s ame r a te r eg a rd l ess o f
t h e i n it i al t re a tm en t s el ec t ed : gl yb u ri d e, ch lo r p rop a mi d e, m e t fo rm i n, o r u lt r a le n t e in s ul in . In al l
t h e m on o th e r ap y t r ea tm en t g ro u ps , p a ti en t s r eq u ir e d ad di t io n al th e r ap ie s o ve r t he st u d y
d u r a ti on . 19 2 At 3 yea r s, < 5 5 % o f p a ti en t s r an d omi ze d to si ng l e p ha r ma co lo g ic th e r ap y co u ld
m a in t ai n a n A 1 C <7 % a nd b y 9 yea r s t hi s d r op p ed t o ~ 2 5% of pa t ie n ts . Th i s is li ke l y du e to th e
n a t u ra l p r og r es si o n o f t yp e 2 d ia b et es in wh i ch β - c e ll fu nc t io n d ec l in es wi t h in c re as e d d u ra ti o n
o f di se as e . Al so , wh e n th e bl oo d gl uc os e b ec ome s ve r y el e va te d , ( F P G >2 5 0 t o 3 0 0 mg / dL ;
p r e p ra n di al gl uc os e c o nc e nt r a ti o ns ≥2 0 0 m g/ d L) , t h e p an c re as ' s a b il i t y to s ec r e te i n su li n i s
d i mi ni sh e d a nd po s tr e cep t o r (p os t bi nd i ng ) de f ec ts in in su l in ac ti vi t y b ec om e m o re im po r t an t .
P o s t re ce p to r de f ec ts a re c ha r ac t e ri ze d b y a re d uc e d r es p on si ve n ess o f t is su e s t o a n y l e ve l o f
i n su li n . I f g l uc os e c on cen t r a ti o ns c an be no r ma lize d , po s t re ce p to r de f ec ts an d p a nc r ea t ic
r e s po ns i ve ne ss to gl uc os e c an b e im p ro ve d . Th is ma y b e r e la t ed to th e hyp o t h es is th a t h ig h
g l uc os e c on ce n t ra t io ns in a nd of t he ms el ve s ma y b e to xi c t o t h e β - ce ll s an d pe r ip h e ra l t is su es
( g l uc o to xi c i t y) . 19 6
Q . R . ' s d et e ri o r at i ng c o ntr o l o n m a xi m um do se s o f g l ip i zid e a f t er 5 yea r s of r e as on a bl e
r e s po ns e f i ts th e d e fi n it io n of se co n da r y f ai lu r e . H o we ve r , t h e s t re ss an d d e p re ss io n a r is i ng
o u t o f he r l i fe si t ua ti o n ha ve n o d ou b t c on t ri b ut e d t o he r p o o r co n t ro l . Th e l a tt e r m a y ha ve le d
t o a c ha ng e i n h e r u su a l c om p li a nc e wi t h di e t, e xe r c is e, an d m ed ic a ti o ns a n d s ho u ld re s ol ve
wi t h t i me an d a pp r o p ri ate ma n ag em e nt . Al t ho u gh h yp e r gl yc em ia ha s b ee n a t t ri b ut e d t o
h yd r o ch lo r o th i a zid e , t he d o se p re sc r ib ed f or Q . R . h as f e w a d ve rs e me t ab ol i c e ff e ct s.
Managing Secondary Failure
H ow s h o ul d Q . R . b e m an a g ed ? S ho u l d s he be sw i tc h ed f r om o r al su l fo n yl u r e a s t o
m e t f o rm i n ?
Q . R . i s e xh i b i ti ng s ym p to ms o f d ep r es si on ( e. g . , l i st l ess n ess a nd fl a t a f fec t ) . He r de p re ss io n
l i ke l y s t a rt e d a f te r he r hu s ba n d 's de a th . E ve r y e ff o r t m us t b e m ad e to add r e ss Q . R . 's
d e p re ss io n b e ca us e i t i s u n li ke l y t ha t s he wi l l b e a b le t o e f fe ct i ve l y i mp l em e nt mo r e a gg r es si ve
t r e a tm en t o f he r di ab e tes un t il he r s i tu a ti o n is imp r o ve d . R es o u rc es th a t m a y be us e d i nc lu de
h e r fa mi l y, a t he r ap is t , an d a so ci a l wo r k e r .
Tr e a t m en t o f s ec o nd a r y s u lf o n ylu r ea f ai lu r e i nc l ud e s i de n ti f yi ng an d c o r rec t in g a n y
d i ab e to g en ic f ac to r s a nd a l te r in g h e r d r u g t he r apy. W he n se co n da r y f ai l ure t o a n y or a l a ge n t
o cc u rs , on e s ho ul d a l wa ys a dd a no t he r a g en t ra th e r th a n s wi t ch to an o the r . Th is is s u pp o r te d
b y a st u d y th a t e va lu a ted t he e ff ec t of m e t fo rm i n a l on e i n a po p ul at i on of p a t ie n ts wh o ha d
f a i le d o r al s u lf o n ylu r e as a n d t h e e f fe ct o f me t fo rm i n p lu s t he su l fo n ylu r ea s . Su bs t i t u ti o n o f
m e t fo rm i n f o r g l ybu r id e d i d n o t p r od uc e a n y s i gni f ic a nt ch an g e i n g l yc em ic co n t ro l, bu t th e
a d di t io n o f m e t fo rm i n t o g l yb u ri d e t he r a p y s ub s tan t i al l y im pr o ve d g lu co se c o nc en t r at i on s. 1 97
A l t h ou gh ma n y c om b in a ti o ns of o ra l a n ti di a be t ic a g e n t s c an be us ed , i t ma k es m o re se ns e t o
m a in t ai n t h e cu r r en t ag en t an d a d d a no t he r r at h er
P . 5 0 -6 6
t h a n t o c ha ng e to t wo n ew m e d i ca ti o ns . O pt i on s fo r Q . R . i n cl ud e th e f ol l owi n g :

A d d in g m e tf o rm in t o t he s u lf o n ylu r ea

A d d in g a ca r b os e t o t h e su l f on yl u re a

A d d in g ro si g li t a zon e o r pi o gl i ta zo n e t o t h e su l fo nyl u r e a
O n e al s o co u ld in t ro d uc e i ns u li n t h er a p y at th is t im e , b u t i t is an un r e as ona b l y c om p li ca t ed
i n t er ve n t io n u nd e r t h e cir c um s ta nc es . Th es e o p tio n s i nc lu d e t he fo l lo wi n g:

A d d in g a n e ve n in g d os e o f in su l in to th e s u lf o n ylu r e a

S wi t c h i ng to in su l in m o no t h e ra p y
I n su mm a r y, p at i en ts suc h a s Q . R. wh o a re u nr es p on si ve t o ma xi m u m d os es o f su l fo n yl u re as
a r e un li ke l y t o r es po n d to mo n ot h e ra p y wi t h m e tfo r m in . F u r th e rm o re , m e tfo r m in al on e i s
u n li ke l y t o b e e f fe ct i ve in p at i en ts wh o s e g l yc emi c c on t r ol ha s d e te r io r a te d s o s e ve re l y t ha t
p a nc r ea t ic r es er ve is lo st a nd r es is ta n ce to in su l in ac t io n i s h ig h (e . g. , F PG > 2 4 0 mg / dL ) .
Th u s , Q . R . s ho ul d n o t be s wi t ch e d t o me t f o rmi n i n li eu o f g li pi zi d e; r at h er , co mb i na t io n t h e ra p y
s h ou l d b e i ns ti t ut e d.
Combination Oral Antidiabetic Therapy
As a n t i c i pa t ed , Q . R . re fu s e s t o c o ns i d e r i n su l in t h e ra p y a t t h i s ti m e. W h i c h c om b i na t i on
o f o r a l a ge n t s i s p r e f e rr e d ?
W hen a ge n ts fr om di f f e re n t a n ti d ia be t ic c l ass e s a r e c om b in ed , th e ir e ff ect s ar e e ss e nt i al l y
a d di t i ve . A t d o sa ge s a ppr o ve d fo r us e i n t he U ni te d S ta t es , a ca r b os e h as b e e n us e d
s uc c ess f ul l y in c o mb in a tio n wi t h b o th su l fo n yl ur ea s a n d me t f o rm in , 12 2 , 1 25 l o we r in g th e A 1 C b y
a p p ro xi m a t el y 1 % . H o we ve r , a n a g e n t t h at c a n be t it r a te d m o re qu ic kl y t ha n ac a rb os e a n d o ne
t h a t i s mo r e l ik el y t o h a ve a p r o fo u nd ef f ec t o n b lo o d g lu c os e co nc e nt r a tio n s sh o ul d b e u se d i n
Q.R.
P i o gl i ta zo n e a nd r os ig li ta zo n e a r e a p pr o ve d f o r u s e i n co mb i na t io n wi t h s u lf o n ylu r ea s . W hen
p i og l it a zo ne wa s ad d ed to su l fo n yl u re a t h er a p y, an im p r o vem en t i n b o th t he F P G an d A 1 C wa s
o b se r ve d : 3 9 t o 5 8 m g/ dL a nd 0. 9 to 1. 3 %, r es pec t i vel y, d ep en d in g o n t he d os e o f p io g li t a zon e
u s ed ( 15 o r 3 0 mg da il y) . P i og li t a zo ne 30 m g a d de d to me t fo r mi n m on o th er a p y r ed u ce d t h e
F P G b y a m e an of 38 m g/ d L a n d t he A 1 C b y 0 .8 % . 1 6 7 W hen r os ig li t a zon e (2 mg B I D ) wa s
a d d ed to a su l fo n yl u re a , t h e A 1 C an d F P G we r e r ed u ce d 1 . 0% an d 4 4 m g /dL , r es pe c ti ve l y,
c om p a re d wi t h t he su l fon yl u r ea al o ne . R os ig li t a zo n e 4 m g d a il y a dd e d t o m e t fo rm i n r e du ce d
A 1 C a nd F P G b y 1 . 0% and 4 0 mg / dL , r e s pe ct i ve l y, c om pa r ed wi t h m e tf o rmi n al on e . 1 6 5 , 1 98
Me t f o r m i n a ls o h as be en u se d s uc ce ss f ul l y i n c om b in a ti on wi t h th e s ul f onyl u r e as wh e n p r im a r y
o r se co n da r y f ai l ur e o ccu r s . Th e co mb i na ti o n l owe r s f a st i ng gl uc os e c onc e nt r a ti o ns
a p p ro xi m a t el y 8 0 m g/ d L a n d A 1 C va lu es b y 2% wh e n m et f o rm in is g i ve n in f ul l d os e (2 , 50 0
m g /d a y in t hr e e d i vid e d d o se s ). 1 97
I n t he l a t er st a ge s o f t h e U K P D S , 5 37 ob es e a n d n o n ob es e p a ti en t s wh o fa i le d s ul f on yl u r ea
m o no t he r ap y we r e r a nd om l y as si gn e d t o c on t in u e s ul f on yl u r ea m o no t he r ap y o r to ha ve
m e t fo rm i n a dd e d. A n i nte n t io n - to - t re a t a na l ysi s o f t hi s su bs t ud y s ho we d t h a t t h os e p at i en ts
a ss i gn e d t o c om bi ne d me t f o rm in –s u lf o n ylu r ea the r a p y ha d a 9 6 % i nc r ea se i n d ia be t es - r el a te d
d e a th s P < .0 3 9) an d a 60 % in c re as e i n a ll - ca us e d e at hs ( P < . 04 1 ) c om pa r e d wi t h t ho se
p a t ie n ts c on t in u ed on sul f o n ylu r ea mo no t he r a p y. 1 9 3 Ho we ve r , o wi n g to th e la ck o f a p la ce b o
c o nt r o l a nd th e i n ab il i t y to us e m as ki n g, th es e det r i me n ta l e f fe c ts h a ve b ee n qu es t io n ed . Th e
A D A c u r re n tl y d oe s n ot re c omm e nd an y c ha n ge in t he cu r r en t g u id el i ne s f o r th e u se o f
c om b in a ti o n me t fo r mi n –su l f on yl u re a th e ra p y un t il a n e w, a pp r op r ia t el y d esi g ne d , ra nd om i ze d
p l ac e bo -c o nt r o ll ed t ri a l ca n de li n ea t e s om e sp ec i fi c m ec ha n ism o f a d ve rs e i n te r ac t io n b e t we e n
t h e t wo d ru gs .
A l t h ou gh Q . R . h as r ec ent l y l os t we i gh t , s he re mai n s o ve r we i g ht . Th us , g l ip i zi de sh o ul d b e
m a in t ai ne d a n d m et f o rm in a dd e d. H o we ve r , be cau s e s tu di e s h a ve su g ge st e d th a t ma xi m u m
m e ta b ol ic ef f ec ts a re obs e r ve d a t g li p i zid e d os es o f 10 m g d a il y, 1 50 Q . R . 's do se ca n b e
d e c re as e d t o t hi s d os e wh i le me t fo r mi n d os es a re s lo wl y i n c re as e d a s d esc r i be d i n Qu es t io n
53.
Combination Oral Antidiabetic and Insulin Therapy
Q . R . t o l e ra t e d s low t i t ra t i o n o f m e t f o rm i n to a m a x im u m d os e of 85 0 m g t h re e t im es da i l y,
w h i le ma i n ta i ni n g a dos e o f g l ip i zi d e 1 0 m g da i l y. T h i s im p r o ve d h e r F P G a n d A 1 C
m o d es t l y f o r a p p r o x i ma t e l y 6 m o n t h s (F P G , 17 0 t o 2 00 mg / d L ; A 1 C , 7. 6 %) . Ac a r b o s e w a s
a d d ed t o h e r th e r a p y, b u t s he w a s d i sc o mf o r t ed b y i t s G I s i de ef f e c ts . H ow e ve r , s he
r e m a in e d s ym p t o m a t i c a n d f in a ll y a g r e e d t o co n s i de r i ns u li n t he r a p y. W h y w o u l d i t b e
r e a s on a b le t o u se i ns u li n i n c om b i na t i on w i t h a n o r al an t i d ia b et i c a ge n t f o r Q . R. ?
W hen a c om bi n at i on of or a l a g en t s f ai ls , i t i s t emp t i ng to ad d ye t a no t he r a g e nt , b u t a s
d i sc us se d p r e vio us l y, the us e o f th r e e o ra l a g en ts in co mb in a ti o n h as n o t b e en e xt e n si ve l y
s t ud i ed . In st e ad , we r eco mm e nd r e ve rs io n t o a si n gl e a g en t i n c om bi n at io n wi t h a si ng l e d os e
o f an in t e rm ed i at e - o r l on g - ac t in g i ns ul i n, o r i ns ul i n m on o th e ra p y i f f as ti ng g l u co se
c o nc en t r at i on s su g ge s t se ve r e in su li n d e fi ci e nc y ( e . g ., F P G >2 00 mg / dL ) .
Th e c om bi n ed us e o f i nsu l in wi t h a va r i et y o f o r al a g en ts ha s b e en e val uat e d , b u t t he st u di es
d i f fe r in th e ir de si g n . I n s om e s t ud ie s , si n gl e d ose s o f an in t er me d ia t e - o r l o ng - ac t in g i ns ul i n
a r e ad de d to a si n gl e o ra l an t id ia b et ic ag e nt in pa t i en ts wh o h a ve d e vel op e d s ec on d a r y f a il u re .
I n o th e rs , o r al ag e nt s a re i ns ti t ut e d i n p oo r l y c o nt r o ll e d p at i en t s t ak in g h ig h do se s o f i ns ul i n
( e . g ., > 70 U /d a y) . Th e p ri m a r y o u tc om es th a t h a ve b ee n e va l ua t ed in cl ude me as u r es o f
g l yc em ic c o nt r ol ( e. g . , A 1 C , F P G ) a n d t h e e xt e n t to wh i c h i ns ul i n d os es h ave b e en de c re as e d.
Th u s , th e c om bi n ed us e o f in su l in an d o r al ag e nts ca n b e c on si d er e d a t bo t h St e p 4 an d S t ep 6
i n th e p r o po se d a lg o r it hm (s e e F ig . 50 - 9 ). Th i s th e r ap e ut ic ap p r oa ch al so mi g ht be us ed as an
i n t er m ed ia t e s te p wh e n e va l u at in g wh e t he r pa ti en t s o n r e la t i vel y l o w t o tal - d ai l y do se s o f
i n su li n c ou l d b e m an ag ed wi t h o ra l a n ti d ia be t ic th e r ap y. 1 99
H ow s h o ul d in s u li n b e c o m bi n e d w i t h o r a l a g en t s , a n d i s th i s c o mb i na t i o n m o r e e f fe c t i ve
t h a n in s ul i n a l on e ?
Insulin Plus Sulfonylureas
S e ve r a l i n ves t ig a to rs have e xp l o r e d t h e b en e fi cia l ef f ec ts of su l fo n yl ur e as us ed in co mb i na ti o n
wi t h i ns u li n , a nd th e re su l ts o f t he i r wo r k h a ve be e n s ub j ec te d t o c r i ti ca l r e vi e ws a nd m e ta a n al ys es . 20 0 , 2 0 1 , 2 02 , 203 P l ac eb o -c on t r ol l ed an d u nc o nt r o ll ed st u di es in di c at e th a t i n so me
p a t ie n ts wi t h t yp e 2 di a be t es wh o
P . 5 0 -6 7
h a ve fa i le d m on o th e ra p y wi t h a s u lf o n ylu r ea o r i ns u li n , t he co mb in a ti o n o f a su l fo n ylu r e a p lu s
i n su li n m a y im p ro ve F P G c on ce n t ra t io ns an d A 1 C va l u es m o de s tl y ( 40 t o 50 mg / dL an d 1 t o 2 %,
r e s pe ct i ve l y) . Th i s m a y o r ma y n o t b e ac co mp a ni e d b y a m od e st de c re ase i n i ns ul in
r e q ui r em e nt ( ap p ro xi m a te l y 2 5% ) . Be ca us e m an y p a ti e nt s t r ea t ed in t he se s tu di es we r e no t
o p t im al l y c o nt r o ll ed on in s ul in be f o re co mb in a ti on t he r a p y wa s i ns t it u te d , i t i s i mp os si bl e to te l l
wh e t h e r c om b in a ti o n t her a p y wa s mo r e e f fe ct i ve t h a n i nt e ns i ve i ns ul i n r eg i me ns . O th e r
p o t en t ia l d r a wb a cks of co m bi n at io n th e ra p y in cl ud e in c re as ed co st s , co mp l e x t h e r ap eu t ic
r e g im en s , a nd a h ig he r ri sk f or h yp og l yce mi c r e ac t io ns .
A p o pu la r r eg im en is bed t im e i ns u li n , d a yti me sul f o n ylu r ea ( B I D S t h er a p y) , a lt h ou g h o ne s h o rt t e r m s tu d y ( 3 mo n th s ) s ug g es ts t ha t m o rn i ng in sul i n a nd in su l in al on e wo rk eq u al l y we l l . 2 0 4
I n ve s ti ga t o rs c om p a re d th e ef f ec t i ven es s o f t h e fo l lo wi n g in su l in re g im ens : (1 ) o ra l
h yp o g l yc em ic t he r ap y p lu s N P H g i ve n i n t he e ven i ng , ( 2) o ra l h yp o gl yc em ic t he r ap y p lu s N P H
g i ve n i n t h e mo r n in g , ( 3 ) N P H a n d r eg u la r in su li n ( 2 : 1 r a ti o ) g i ven t wi c e da i l y, (4 ) re g ul a r
i n su li n b e fo r e m ea ls an d N P H a t b e dt im e , a nd ( 5 ) c on t in u ed o ra l h yp og l yce m ic d r u g t he r a p y
( t h e c on t r ol gr o up ) . Al l t re a tm e nt r eg im e ns we r e e q u al l y e f f ec ti ve in ac hi evi n g gl yc em ic
c o nt r o l; ho we ve r , t h e a dd i t io n o f N P H a t b e dt im e wa s a ss oc ia t ed wi t h le ss we i g ht g ai n a nd
h yp e r in su l in em i a. A m e ta - a na l ysi s o f s im il a r t r ia ls co n fi rm e d t h at c om b ina t i on th e r ap y wi t h
i n su li n a n d s ul fo n yl u re a m a y be mo r e a pp r o pr i at e t h an in su l in m o no t he r apy i n t yp e 2 d i ab e te s
p a t ie n ts wh o ha ve de ve lo p e d p ri ma r y o r s ec o nd ar y f a i lu r e . 2 01 I ns ul in gl ar g i ne ca n a ls o b ee n
u s ed wi t h a su l fo n yl ur e a. 2 0 5 , 2 0 6
Insulin Plus Metformin
Th e c om bi n ed us e o f i nsu l in an d m e tf o rm i n h as no t be e n s tu di e d e xt e n s i ve l y, bu t wh e n
m e t fo rm i n is ad d ed to ins u li n t h e ra p y or vi ce ve rs a , m ea su r es o f gl yc em ic co n t ro l im p r o ve a nd
i n su li n re q ui r em en t s d ecr e a se . I n a d ou bl e - bl in d , p l ac eb o -c on t r ol l ed s t udy o f 5 0 o be se pa t ie n ts
wi t h t yp e 2 d ia be t es po or l y c on t r ol le d wi t h i ns ul in mo n ot h e ra p y, m e tf o rm in ( 8 50 m g t wi c e da il y)
o r pl a ce bo wa s ad d ed to i ns u li n f o r 6 m o nt hs . Me t f o rm i n si g ni f ic an t l y i mp ro ve d al l g l yce mi c
i n di ce s (A 1 C de c re as e d 1. 8 % ; m ea n p la sm a g lu c os e d ec r e as ed 74 mg / dL ve r s us no ch a ng e i n
t h e p l ac eb o g r ou p ) a n d d e c re as e d me a n i ns ul in r e q ui r em e nt s b y 2 5% . Ch o le s te r ol an d
t r i gl yc e ri d e l e vel s a ls o w e r e i m pr o ve d, es p ec ia ll y i n t h e 1 4 s ub je c ts wh o re s po n de d p a r ti cu la r l y
we l l t o m e tf o rm in . Th os e s ub j ec ts wh o di d n o t r esp o n d as we l l (1 3 ) h ad hig h e r m ea n p la sm a
g l uc os e c on ce n t ra t io ns (> 1 8 0 mg / dL ) . 20 7
A l t h ou gh me t fo r mi n i s a n a n ti h yp e rg l yce mi c a ge n t, o ne mu st be al e r t f o r i nc r e as ed
s us c ep ti b il i t y to h ypo gl yc e m i a wh e n it is us ed in c om b in a ti o n wi t h in su l in . S t u di es se em to
c o nf i rm po t en t ia l a d va nta g es of me t fo r mi n o ve r su l f on yl u re as wh e n us ed in co mb i na t io n wi t h
i n su li n . Th es e i nc lu de i ts f a vo r ab l e e ff e ct s o n t he l i pi d p r of i le , i ns u li n c onc e nt r a ti o ns , a nd la ck
o f we i g ht ga i n. Th e ri sk fo r h yp og l yce mi a m a y a lso b e l o we r wi t h m e tf o rm in . 1 93 , 20 8 , 2 0 9
Insulin Plus TZD
I n a r a nd om i ze d, pl ac e bo - c on t ro l le d s tu d y, 56 6 typ e 2 d i ab e ti c p at i en ts t re a t ed wi t h i ns u li n
( m e an in su li n d os e , 6 0 .5 U / d a y) we r e ra n do mi ze d t o t re a tm en t wi t h 1 5 o r 3 0 m g p i og li t a zo ne or
p l ac e bo i n ad di t io n t o the i r i ns u li n . Tr e a tm e nt wi t h p io gl i ta zo n e p lu s i ns ul in r e du ce d A 1 C va lu es
b y 1 . 0% f or t he 15 - mg do s e a nd 1. 3 % f o r t h e 3 0 -m g d os e c om p ar e d wi t h b a se li n e; F P G va lu es
d e c re as e d 3 4. 5 m g/ d L an d 48 . 0 mg / dL f o r t he 15 m g a nd 30 mg do se r esp e ct i ve l y. 2 1 0
Insulin Plus an α-Glucosidase Inhibitor
Th e a d di t io n o f a ca r b os e o r m i gl i to l t o i ns u li n t h er a p y h as m od es t ef f ec ts o n m e as u re s o f
g l yc em ia an d i ns u li n r e qu i r em en t s. In a m ul t ic en te r , r an do mi ze d , d o ub le -b l in d , p la ce b o c o nt r o ll ed t ri a l, 21 9 m en a n d wo m e n wi t h t yp e 2 d i ab e te s t r e at e d wi t h in su l in r ec ei ve d 2 4
we e k s of t re a tm en t wi t h a c a rb os e o r pl ac eb o . Pat i e nt s we r e i ni t ia t ed on ac a r bo se 50 m g th r ee
t i me s d ai l y, an d d os es we r e i n cr e as ed a t 6 - we e k i n t er va l s t o 3 00 m g th r ee t im e s d ai l y.
C o m pa r e d wi t h th e pl ac eb o g ro up , th e A 1 C de c re as e d b y 0 .4 % a n d d ai l y i ns u li n r e qu i re m en ts
d e c re as e d b y 8. 3 % i n t he ac a r bo se g ro up ( P < . 00 0 1 ) . 1 26 A s im il a r i mp r ove m e nt in A 1 C wa s
o b se r ve d i n a n ot h er co n tr o l le d t r i al i n wh i ch pe o pl e wi t h i ns u li n -t r e at e d t yp e 2 d ia b et es
r e c ei ve d a ca r bo se ( 15 0 to 6 00 m g ) f o r 1 ye a r. 1 25 A 6 -m o nt h , d ou b le - bl i nd, p la ce b o -c on t r ol le d
t r i al in 11 7 s u bj ec ts wi t h t yp e 2 d ia be t es t re a te d wi t h i ns u li n d em o ns t ra t ed a 1 . 3% r ed uc t io n i n
A 1 C va l ue s wi t h t he ad d iti o n o f m ig l it ol 1 00 m g t h re e ti me s d ai l y ve r su s p lac e bo .
I n Q . R . ' s ca s e, it ma ke s t h e m os t s en se t o d isc o nt i n ue th e s ul f on yl u r ea and t o a dd a s in gl e
d o se of in t e rm ed i at e -a c tin g in su li n to m e t fo rm i n th e r ap y ( s ee s u bs eq u en t d i sc us si on ) .
A d va n t ag es at t r ib u te d t o a d di ng in s ul in to an o ra l a g en t a s t h e “ n e xt s te p ” a f t er f ai lu r e , as
o p p os ed to us in g i ns u li n a l on e , i nc lu de t he fo l lowi n g 2 0 6 , 2 1 1 , 2 12 :

L o we r i ns ul i n d os ag es ca n be us ed , a n d t hi s m ini m i zes we i gh t g a in an d hyp o g l yce mi a .

S i m pl e r, si ng l e -d os e i nsu l in r eg im e ns a r e p os si bl e ( ve rs us m o no t he r a p y wi t h i ns u li n ) .

L o we r i n g t he f as ti n g g luc os e c o nc en t r at io n s im pr o ve s g l uc os e c on t ro l th ro u g ho u t t he
d a y b ec au se gl uc o se e xc u rs i on s r el a t ed to m e al s a re la ye r e d o ve r l o we r va l u es .
F u r t he r mo r e, lo we r g l uco s e va l ue s im p r o ve β - ce ll r es p on si ve ne ss to gl uco s e a nd
e n h an ce ti ss ue r es po ns ive n e ss to in su li n a c ti o n.

U s e of th e i ns u li n s en si t ize r s ma y e nh an c e t he eff e c t o f e xo g e n ou s i ns ul in wh i l e
m i ni mi zi ng we i g h t g ai n an d h ype r in su l in em i a. The y a ls o m a y ha ve be n ef ic i al ef f ec ts on
l i pi d p r o fi le s a n d o th e r ca r d io va sc ul a r d e fe c ts .
Th e r e f o re , gl ip i zi de s h oul d be di sc on t in u ed an d m e t fo rm i n ma i nt a in e d; Q. R . sh o ul d b e s ta r t ed
o n 5 t o 1 0 u ni t s o f N P H , L e n te , u l t ra l en t e , o r i ns ul i n g la r gi n e a t b e dt im e . Th i s do se is ba se d o n
e m pi r ic us e o f i ns ul i n in a va r i et y o f s tu d ie s ( 0 .1 t o 0 .3 5 U/ kg ) 2 13 an d a co n se r va t i ve es t im a te
f o r ba sa l i ns u li n o f a p pr oxi m a t e l y 0 .5 U /h o u r ( Q . R. we i g hs 1 40 po un ds , o r 6 4 k g ) . Th e do s e
a l so ta ke s i n to acc o un t th e po ss ib il i t y th a t Q . R. is se c re t in g s om e b as al in s ul in o f h e r o wn a nd
wi l l h a ve s om e r es i du al s t im ul a ti o n o f i ns ul i n se cr e t io n b y g li p i zid e . Th e N P H d o se s h ou ld be
a d ju s te d u p wa r d we e kl y i n 5 - u ni t i nc r em e nt s ( d epe n di n g o n i nd i vi du al r esp o ns e t o i ns u li n ) u n ti l
a d es i ra bl e FP G c on ce n tr a t io n i s o b ta i ne d ( p r ef e ra b l y <1 2 6 mg / dL ) . If th e re is no im p ro ve me n t
i n gl yc em ic c on t r ol af t e r 3 mo n th s , Q . R . s h ou l d be co n ve r te d to m u lt i pl e da i l y in su li n i n je ct i on s
( s e e Q u es t io n 6 1 ) .
A n a lt e rn a ti ve f o r Q . R . i s t o di sc on t in ue al l o r al ag e n ts a n d b eg i n i ns ul in m o no t he r ap y u si n g
m e th o ds s im il a r t o th os e d es c ri b e d fo r t ype 1 p a ti e n ts . Thi s o p ti o n al s o is r a t io n al b a se d
P . 5 0 -6 8
o n th e o bs e r va ti o n t ha t p a t ie n ts l ik e Q . R . a r e li ke l y t o r e qu i re in su l in th er a p y b ec au se of
p r o g re ss i ve β - c el l f ai l u re. F u r th e rm o re , i ns u li n mo n o th e ra p y ma y b e l es s e xp e n s i ve a n d e as ie r
t o as se ss th an co mb i na t io n o ra l + in su li n th e ra p y. N e ve r t he le ss , m an y c lin i ci an s u se si ng l e
d o se s o f i ns ul i n i n co mb in a t io n wi t h o r al ag en t s as a b r id g e t o e ve n tu al ins u li n m on o th e ra p y,
e s pe ci a ll y f o r t ho se pa t ie n ts un wi l l in g to ad h er e t o mu l ti pl e d a il y i ns u l in in j ec t io ns .
Insulin Monotherapy in Patients With Type 2 Diabetes
Insulin Regimens
Q . R . ' s N P H in s ul i n d o se w a s e ve n t u al l y t i t r a t e d t o 25 un i t s a t b e d ti me . I n c om b i na t i on
w i t h m e tf o r m in 85 0 m g t h r e e ti m es da i l y, h e r f a s t i ng g lu c os e l e ve l s fe l l t o t h e 1 20 s a n d
1 3 0 s o n m os t oc c as i o ns ; h e r A 1 C d r o p p e d t o 7. 5 %. H o w e ve r , a f te r 1 ye a r , sh e b e ga n to
n o t e a g r ad u al r i se i n gl u c os e co n ce n t r at i o ns t h r o u g ho u t th e da y. T h i s r e su l t e d i n a
f u r t h e r in c r ea s e i n h e r b e d t im e N P H to 40 un i ts ( 0 .6 2 U /k g ) . C u r r e n tl y, h e r m o r n in g
g l u c os e c o nc e n t ra t i on s a r e 14 0 t o 16 0 m g /d L , a n d gl u co s e c o nc e nt r a ti o n s m ea s u r ed
b e f o r e o r a f te r me a ls ra n g e b e tw ee n 1 7 0 a n d 2 0 0 m g /d L . A r e c en t A 1 C va l u e w as 8 .8 %. F o r
t h e pa s t 6 mo n t hs o r so , Q . R . ha s n o t ed i nc r ea s i ng f a ti g u e, bo u t s o f b l u r r e d vi si o n , a nd
r e c u r r e nc e o f he r m on i li a l in f e ct i o ns . H ow s h ou l d sh e b e m a na g e d n ow ?
Th e n e xt s t ep in ma na g in g Q . R . ' s di a be t es is t o in s ti t u te i n su li n m on o th e ra p y. B ec au s e p eo pl e
wi t h t yp e 2 d ia be t es r et ai n s om e p a nc r ea t ic fu nc ti o n , i t o f te n i s p oss i bl e to ac h ie ve an
a cc e pt a bl e l e ve l o f c on t ro l wi t h o nc e - o r t wi ce - d ai l y d os es o f in t er me d ia t e - o r lo ng - ac t in g
i n su li n i n c om bi n at i on wi t h r ap i d t o sh o r t -a ct i ng in s ul in s . U n f or t un a te l y, la r g e d os es of in su l in
( 0 . 7 t o 1 . 0 U/ kg pe r da y) o f t en ar e n e ed e d b ec aus e th es e p a ti en t s a r e r esi s ta n t t o i ts ac t io n .
Th u s , we i gh t ga in an d the p ot e nt i al fo r h ypo g l yc em i a ac co mp a n y gl yc em ic c on t r ol .
F u r t he r mo r e, i t ma y b e di f f ic ul t to ac hi e ve a cc ep ta b le gl yc em ic c o n tr o l wi t h i ns ul in in a “ r e al wo r l d ” si t ua t io n . St u di es o f pa t ie n ts wi t h t ype 2 d ia b e te s wh o we r e c a re d fo r wi t h i n a h e al t h
m a in t en a nc e o rg a ni za t ion su g ge s t t ha t p a ti e nt s m a na g ed wi t h i ns u li n u se mo r e m ed ic a l
r e s ou r ce s t ha n d o p a ti e nt s t re a te d wi t h o r al ag ent s — at le a st wi t h in th e 2 ye a r s o f s t ud y. A 1 C
va l u es de cl i ne d b y a m ea n of 0 .9 % a t 1 ye a r, bu t o n l y 4 0 % ac h ie ve d a n A 1 C < 8% . 21 4 W he th e r
i n su li n th e ra p y wi l l tr a nsl a t e i nt o l o ng - te r m c os t sa vi n gs in th e c a re o f p eop l e wi t h t yp e 2
d i ab e te s b y d el a yi ng th e o ns e t a nd p ro g r ess i on of c om pl ic a ti on s r e ma in s a n un a ns we r e d
q u es t io n . 2 1 5
Typ i c a l l y, t yp e 2 di a be t es pa t ie n ts ar e i n it i at e d on t wi c e -d a il y d os es o f s pl i t -m i xe d in su l in . L ik e
t yp e 1 p a ti en t s, pe o pl e wi t h s e ve re t yp e 2 d is e as e m a y r eq ui r e re gu l a r in s ul in , in su li n l is p r o o r
i n su li n a sp a r t b e fo r e mea l s t o m in im i ze p os t pr a nd i al e xc u r si on s . I ns ul i n l is p r o h as b e en s h o wn
t o de c re as e p os t p ra n di al g l uc os e c on ce n tr a ti o ns t o a g r ea t e r e xt e n t th a n r e g ul a r i ns ul i n ( 3 0%
l o we r a t 1 ho u r a n d 5 3% l o we r a t 2 h o u rs ) a n d wa s a ss oc i at e d wi t h a l o we r r a te of
h yp o g l yc em i a, pa r t ic ul a rly b e t we e n m i dn ig h t a nd 6 A M ( 3 6 % ) . Ho we ve r , A 1 C l e vel s we r e n o t
s i gn i fi ca n tl y d if f e re n t a f te r 6 m on t hs . 21 6 A si mi lar r e sp on s e wi t h in su l in as p a rt wo u l d b e
e xp e c t e d . O n e s ho ul d b e a wa r e t ha t wh e n h ig h do s es o f in su li n a r e u se d , p a ti e nt s h a ve
d i f fi cu l t y l o si ng we i g ht . Th i s is s ec o nd a r y to th e a n a bo li c e f fe ct s o f i ns u lin a nd th e h u ng e r t h at
c a n oc c ur in as so ci a ti on wi t h h yp o gl yc em ia . Th e re a ls o is co nc e rn ab o ut th e po t en t ia l
a t h e ro ge n ic c o ns eq ue n ce s o f c h r on ic al l y el e va ted i n s ul in le ve ls , bu t th is h a s n ot be e n
e s ta b li sh e d. 2 17 , 21 8 I n pa t i en ts li ke Q . R . , l o we r i ng g lu co se co nc en t r at i on s i s t h e f i rs t p r io r it y.
A s de sc r ib e d i n Q u es t ion 6 , wh ic h a d dr es s i ni t iat i o n o f i ns ul i n t he r ap y i n t yp e 1 p a ti en t s, on e
c o ul d b e gi n wi t h a c on ser va t i ve to t al da i l y d os e of 0 . 5 U / kg pe r d a y as N PH a n d r e gu la r in su l in
s p li t i n to t wo d os es (t wo - t h i rd s i n t h e mo r ni n g a nd o ne - t hi r d i n t he e ven i ng ) . H o we ve r , Q . R . i s
a l r ea d y us in g 0 . 62 U /k g p e r da y. Th e r ef o r e, th is d o se s h ou l d b e sp l it ( e. g. , 1 8 u ni ts N P H / 10
u n i ts re g ul a r i ns ul in in t he mo r n in g a nd 6 u ni t s NP H / 6 un i ts re g ul a r i ns ul in i n t he e ven i ng ) an d
t h e e f f ec ts e val ua t ed t hro u g h mo r e f r e qu en t S MB G . Q . R . sh o ul d b e i ns t r uc t ed t o i nj ec t t h e
r e g ul a r / N P H i ns ul i n mi xt u r e 30 m i nu t es b e fo r e b re a kf as t an d d in n e r. I f she we r e t o u se a
p r e mi xe d i ns ul i n wi t h ei th e r i n su li n a sp a r t o r l is pr o , s h e wo u l d n e ed to in je c t t h e i ns ul in
i mm e di a te l y be f o re ea t ing ( wi t h i n 1 5 mi n ut es o f ea t i ng ) .
Premixed Insulins
Q . R . h a s d i f fi c u lt y m i x i n g h e r N P H a nd r e gu l a r i n s ul i ns . E ve n w i th r ep e a t ed ed u ca t i on ,
s h e c o n t in u es t o m ak e d o s i ng e r r o rs a nd he r vi a l o f r e gu l a r i n s ul i n i s c o n si s t en t l y
c l o u de d . H e r cu r r e n t i ns u l i n r e g im e n i s a s f o l low s : N P H 20 U / r eg u l a r i n s u li n 1 0 U i n t he
m o r n i ng a nd N P H 6 U / re g u la r i ns u l in 10 U i n th e e ve n in g . W h at a r e op t i o ns f o r Q . R .?
S e ve r a l o p ti on s a r e a va ila b le f o r in d i vid u al s wh o h a ve di f fi cu l t y m i xi n g N PH a n d s ho r t -a c ti ng
i n su li ns . Th e f i rs t i s t o pr e sc r ib e a f i xe d , m i xe d do s e o f N P H a nd r eg ul a r in s ul in . In t he U ni t ed
S t a t es , f i xe d mi xt u r e s of N P H a n d r eg u la r in su li n i n a 70 : 30 r at i o a nd a 50 : 5 0 r a ti o a r e
a va i la b le (s e e Ta b l e 5 0 -8 ) . In E u ro p e, m a n y ot h er f i xe d r a ti os a re a vai la bl e . Co mm e rc ia l
c om b in a ti o ns o f th e ra pid - a ct i ng in su li ns pl us an i n te r me di a t e - ac t in g i ns ul i n a ls o a r e a va il a bl e :
H u m al o g Mi x 7 5 / 2 5 ( a m ixt u r e o f in su l in li sp r o p lus N P L - n eu t r al p ro t am ine l is pr o ) a n d N o vo lo g
Mi x 7 0 / 3 0 ( a mi xt u r e o f in s ul in as p ar t pl us N P H ) . Th e b ig g es t a d van t a ge o f p re mi xe d i ns u li ns
i s c on ve n ie nc e , e sp ec ia ll y f o r p a ti e nt s wh o a dm in i st e r t h ei r in je c ti on s a wa y f r om h om e.
A n o t he r i mp o r ta n t a d vant a g e is ac cu r ac y. A s Q . R. i ll us t r at es , a l ar g e p e rce n t ag e o f p a ti e nt s
m ak e e r r o rs in m e as u ri ng a nd m i xi n g in su li n , e spe c ia ll y t h e e ld e rl y. I de al ly, t h e ra t io of N P H
a n d p r an d ia l i ns ul i n sh ou l d b e i nd i vi du a li ze d f o r e a ch pa t ie n t. P r ac ti ca l l y, h o we ve r , t he r e a r e
o cc a si on a l p at i en ts in wh o m t he f i xe d , m i xe d p rod u ct s m us t b e u se d t o p ro vi d e b o th th e ra p id a c ti n g ac t io n o f re g ul a r , i n su li n l is p r o, o r as p a rt in s ul in an d th e m o re pr o lo n g ed ac ti o n o f N P H .
Th e o ns e t a nd du r a ti o n o f ac t io n o f t h es e f i xe d m i xt u r e s is id e nt ic a l wi t h t h a t ac h ie ve d wh e n
t h e p r a nd ia l i ns u li n a nd N P H i n th e s am e d os es a r e ad mi ni s te r ed b y s e pa r a t e i nj ec ti o n . I n
a d di t io n , i t i s n o w p os si bl e to pu r ch as e p r e fi ll e d syr i n g es c o nt a in in g th es e f i xe d m i xt u r es .
C u r r e n tl y, Q . R . ' s e ve ni ng d os e o f i ns ul i n e xc e e ds t he 70 : 30 r at io o f t he pr e m i xe d in su li n a s
we l l a s t he 50 : 50 r a ti o . Th e r e fo r e, i f Q . R . i s e li g ibl e fo r vis i ti n g n u rs in g s ervi c es o r i f s he li ve s
wi t h s om e on e wh o c an be t au g ht ho w t o mi x i n s uli n s, se ve r al s yri n ge s c an b e p r e dr a wn f o r h e r
a n d p la c ed in th e re f ri g er a t o r . I ns ul i n st o r ed in thi s wa y i s s ta bl e fo r u p to 3 mo n th s. 7 8
Insulin Plus Oral Antidiabetic Agents
Q . R . ' s da u g ht e r w as i ns t r u c t ed on h ow to p r ed r aw i n su l i n s yr i n g e s fo r h e r m o t he r . O ve r a
p e r i o d o f 2 m on t h s, Q .R . ' s gl yc e m i c co n t r o l ha s s te a di l y i m p r o ve d w i t h mu l t i pl e in s ul i n
a d j us t m en t s .
P . 5 0 -6 9
H e r c u r r e nt d os e i s 3 6 u n i t s N P H/ 1 2 u n i ts r egu l a r in s u li n in t he mo r ni n g , a n d 1 0 u n i ts
N P H / 1 8 un i t s r e g ul a r ins u l i n b e fo r e di n ne r . S he n ow pe r f o r ms SM B G ; f a s t i ng b lo o d
g l u c os e c o nc e n t ra t i on s r a n g e f r o m 1 40 t o 1 60 m g / d L ; h ow e ve r , p r e p ra n d ia l bl o o d g l uc o se
c o n ce n t r a ti o ns r a ng e f ro m 12 0 to 20 0 m g / dL . Al s o , d e sp i t e e a r ne s t a t te m p t s t o c o mp l y
w i t h h e r m ea l pl a ns , Q .R . h a s g ai n e d 1 2 l b s i nc e be g i nn i n g i ns u l in mo n o t he r a p y. W h a t
a r e t he r a pe u t i c o p ti o ns f o r Q . R . ? I s i t r a t io n al t o a dd a n i ns u l in se n s iti z i ng d r ug t o Q . R. ' s
t h e r a p y?
Q . R . ' s gl yc em ic co n tr o l re m ai ns un sa t is f ac to r y d es p it e a ve r y hi g h t o ta l -d ai l y d os e o f i ns ul i n
( 1 . 1 U /k g p er da y) . F u rt he r m or e , t h es e h ig h i ns ul in d os es ar e c on t r ib u ti n g t o he r we i g ht ga i n. I f
Q . R . i s mo t i va te d a nd abl e , o n e o pt i on is to “i n ten s if y” h e r i ns ul in t he r ap y. B y p r o vid i ng do se s
m o r e p h ys i ol og ic a ll y, i t m a y be po ss i bl e t o d ec re a se he r to t al da i l y d os e. F o r e xa m p le , on e
c o ul d c on si d er a ug me n tin g Q . R . ' s e nd og e no us ins u li n wi t h sm al l b o lu se s o f in su l in li sp r o o r
a s pa r t wi t h e ac h m ea l ( e. g . , 5 to 7 u ni t s o r 0 . 1 U /k g ) a cc om pa n ie d b y l o we r d o s es o f N P H o r
U l t r a le n te (e . g ., 0 .3 5 U/ kg p e r d a y) s pl i t e qu al l y in t o 1 2 u n it s i n t h e mo r nin g an d a t b e dt im e o r
a si n gl e d os e o f i ns u li n g l a rg i ne to p ro vi d e h ig her b as a l l e vel s. Th is is bas e d o n a to t al - da i l y i n su li n re q ui r em en t of app r o xi m a t el y 0 .7 U /k g p e r d a y, wi t h th e b as al do se c om p ri si n g 5 0% of
t h e to t al do se . I n su li n l isp r o an d a sp a r t d os es wou l d b e a dj u st e d b as ed on 2 - ho u r p os t pr a nd i al
l e ve ls ( 10 0 t o 1 4 0 mg / dL) , a nd c a r bo h yd ra t e i n tak e a n d N P H d os es wo u ld b e b as e d o n g lu co se
c o nc en t r at i on s me a su r ed b ef o r e d in ne r (m o r ni ng N P H ) a nd in t he m o rn i ng ( b ed t im e N P H ) . 21 6
Ma n y o t h e r in su l in re g ime n s co u ld be us ed , bu t i t o f t en i s p os si b le to a void p e ri od s o f
h yp e r in su l in em i a a nd m in i mi ze in su li n d os e re q uir e m en ts b y us e o f t hi s s tr a t e g y.
A s ec on d o p ti o n is t o sim p li f y Q . R . ' s i ns ul in r eg im e n b y co n ti n ui ng he r p re s en t m i xe d d os es o f
N P H a n d r e gu l ar in su l in ( s e e f ol l o wi ng di sc us si on ) a nd to t r y i m pr o vi ng co n t r ol wi t h l o we r
d o se s b y a dd in g p i og li t azo n e 15 o r 3 0 mg on ce da i l y or r os ig l it a zo ne 4 mg o nc e d ai l y. W hen
F P G c on ce n t ra t io ns r ea ch ≤ 1 20 mg / dL , i ns u li n d os es sh o u l d b e d ec r ea se d b y 1 0% t o 2 5% . O ne
s h ou l d b e a wa r e th a t TZ D ' s o ns e t o f a ct io n occ u rs g ra d ua ll y a nd t ha t m a xi m um e f f ec ts m a y no t
b e ob se r ve d f o r 6 to 8 we e ks . Th e p ri m ar y o bj ec ti ve o f t h er a p y i s t o a ch i eve m e ta bo l ic c o nt r ol .
A n o t he r op ti o n wo u l d b e t o r ei ns t it u te me t fo r mi n . W eigh t l os s i s a s ec on d ar y o b j ec ti ve an d m a y
b e im po ss ib l e t o ac h ie ve.
Reusing Insulin Syringes
A. M . , a 45 - ye a r - o l d w om a n w i th t yp e 2 d i a b e te s , ha s b e en us i n g i nsu l i n 2 0 u n i t s N P H f o r
t h e pa s t 5 ye a r s . I n t h e c o u r se o f h e r vi si t , s he d i sc l os e s t h at s he r eu s e s h e r d i sp o sa b l e
i n s u li n s yr i n g e s t h r ee to f o u r ti m es be f o r e d i sc a r d i ng t he m . I s t h i s p ra c t i ce sa f e?
Th o s e wh o wo r k wi t h p a ti e n ts wi t h d ia b et es kn o w t h a t t he y a r e e xt r e m el y r e s ou r ce f ul i n c u tt i ng
t h e ir h ea lt h c a re co st s . A f r e qu e nt l y en co u nt e r ed p r ac ti ce is th e re us e o f d is p os ab l e s yr in g es .
I n a s ur ve y o f 2 5 4 a du l t in s ul in us e rs , 4 5 % r e us ed t he i r s yr i ng es fo r an ave r a g e o f f o u r d a ys,
1 6 % re f ri g e ra t ed th e ir s yr i n ge s b e t we e n us es , and 3 5% wi p e d t he i r n ee d le s wi t h a lc o ho l.
D u l l ne ss wa s t h e ma j o r re a so n f o r c ha n gi n g t o a n e w s yr i n ge . Bo r d er s a nd co l le ag u es
e xa m i n e d a pp r o xi m a te l y 2 , 8 00 in je c ti on si t es , a nd n o i nf ec t io n wa s n o te d. 2 1 9
Th e A D A d oe s n o t e nc our a g e t h e r eu s e o f s yr in ge s , b u t o ff e rs gu i de li n es f o r pa t ie n ts wh o
c h oo se t o d o so . Th e y r ec om me n d t h at pa t ie n ts in s pe ct in j ec ti o n si t es fo r r e d ne ss o r s we l l i ng
a n d t o d is ca r d s yr i ng es in t o p u nc tu r e - re si s ta n t, di s po sa b le c o nt a in e rs i f th e y a r e d ul l , b en t , o r
h a ve c o me i n c o nt ac t wi th su r f ac es ot h er t ha n t he sk in . S om e o f t he sm all e r 3 0 - a n d 3 1 -g au g e
n e e dl es s e em p a r ti cu l ar ly s u sc ep t ib l e t o b en d in g a n d ca n fo r m h oo ks . The y d o n o t r e co mm en d
r e f r ig e r at i on or wi p i ng the n ee dl e wi t h a lc o ho l b et we e n u se s, on l y r ec ap p in g . Pa t ie n ts wh o
r e u se th e ir s yr in ge s s hou l d i ns pe c t t he i r s ki n f o r s i gn s o f i n fe ct i on . 69
Cardiovascular Effects
J . A. a 4 7 - ye a r - o l d m an w a s d ia g n os e d w i t h t yp e 2 di a be t es w h e n h e de ve l o p ed “ v e r y h i g h
b l o o d s u ga r s i n t he 30 0s ” w h il e b e i ng t r ea t e d fo r a f oo t in f e c ti o n . H e s t a t es he h as ha d
“ b o r de r l i ne d ia b et e s” fo r > 1 0 ye a r s . O t h e r m ed i c a l p r o bl e ms in c l ud e h yp e r t e n s i o n a n d
m i l d C H F, w h ic h is cu r r e n t l y w e l l c o n t ro l l ed on b e na z ep r i l (1 0 m g d a i ly) , f u r o s e m i de ( 40
m g da i l y) , a n d di g ox i n ( 0 . 2 5 m g d a il y) . F o r t h e p a s t 3 m o n th s , h e h a s a d h e re d t o a l ow - f a t
d i e t a n d e x e rc i se p r og ra m an d ha s m a na g ed t o l o s e 1 0 p ou n d s ( J . A. is c u r r en t l y 5 ′ 9 ″ t a l l
a n d w e ig h s 1 90 po u n ds; B M I 2 8 .1 kg / m 2 ) . F P G c o n ce n t r a ti o ns m e a su r e d o ve r t he pa s t 2
m o n t hs w e r e 1 60 mg / d L a n d 1 4 5 m g/ d L . L i ve r an d r e na l fu n c ti o n te s ts a r e w i t h in no r m a l
l i m i ts . H ow w i ll J. A. ' s ca r d i o va sc u l a r h i st o r y a f f e c t th e c h o ic e o f o ra l a g e n ts ? T h e
p a c ka g e i n se r t f o r a l l su l f o n yl u r e a s i n c lu d es a s p ec i a l w a r n i ng on i ncr e a s ed r i sk o f
c a r d i o vas c u la r mo r t a l ity. W h a t i s t he ba s is o f t h i s w a r ni n g? Ar e s u l f on yl u r e a s
c o n t r ai n d ic a te d in p at ie n t s s u ch as J . A. w i t h a h i st o r y o f c a r d i o va scu l a r di s ea s e?
B e c au se J . A . ' s C H F is un d e r t r ea t me n t, t he us e o f me t fo r mi n i s n ot r ec om me n de d . Th i s i s
b e ca us e wh e n m et f o rm in - a ss oc i at e d ca s es o f l ac ti c a ci d os is we r e a n al yze d , vi r tu a ll y a ll
p a t ie n ts h a d co n cu r r en t c o nd i ti on s t h at p re d is pos e d t he m t o th is po t en t ial l y f at a l c on di t io n .
O n e o f t he se wa s cl in ic al l y si g ni f ic an t C H F, a c on d i ti on t ha t c ou l d d ec r eas e c i rc ul a ti o n t o t he
p e r ip h e r y, t he r e b y p r e dis p os in g t h e p at i en t to ana e r ob ic me t ab ol is m . 2 20 , 2 2 1 Al t ho ug h TZ D s
s h ou l d n ot be us ed in pat i e nt s wi t h N YH A c l as s I II o r IV h ea r t f a il u re , p r act i t io n er s o f te n a vo i d
t h e ir us e a l to g et h er in pa t i en ts wi t h he a r t f ai lu r e b ec a us e o f a c o nc e rn for C H F e xa c e r ba t io n
( s e e q ue st i on 66 ) .
S u l f on yl u re as a re no t c on t r ai n di ca t ed in in d i vid ua l s wi t h a h is t or y o f c a rdi o va sc ul a r d is ea s e.
H o we ve r , t h e F D A r eq u ire d al l m an u fa ct u r er s o f su l f on yl u re as t o i nc lu de in t he i r p ac ka g e
i n se r ts a s pe ci al “ bl ac k b o x” wa r n i n g p re sc r ib e rs o f an i n cr e as ed r isk f or c a r di o vas cu l ar
m o r ta li t y. Th i s wa s ba sed o n a n u ne xp e c t ed f in din g of t he U ni ve r si t y G r ou p D ia b et es P r og r am
( U G D P ) s t ud y i n 1 9 7 0 . Th i s wa s a c oo p e ra ti ve , pr o s pe ct i ve s t ud y t o e va lua t e th e e f fe c ti ve ne ss
o f an t id i ab e ti c t he r a p y i n p r e ve nt i ng vas cu l a r a nd o t he r la t e co mp l ic at i on s o f di ab e te s i n m il d
t yp e 2 d ia b et ic pa t ie n ts . U n e xp e c t ed l y, t wi ce as m a n y c a rd i o vas cu la r de at h s o cc u rr e d i n t he
t o l bu t am id e - tr e at e d g r oup t ha n i n th e p la ce b o - an d in su li n - t re a te d g r ou ps. 2 2 2
A f t e r p u bl ic a ti on o f t he U G D P r e s ul ts , a g r ea t co n t r o ver s y r eg a rd i ng th e s t ud y' s va li di t y a nd
c l in ic al im pl ic a ti o ns a p pe a r ed in bo t h t h e p ro f ess i on al an d l a y p re ss ; th es e a r e s um ma r i zed
e l se wh e r e . 22 3 G ro wi n g e vi d e nc e t ha t n o rm a li za ti o n o f g l uc os e co n ce n tr at i o ns m a y in fa c t
d e la y l on g - te r m c om pl ica t i on s, an d th e f a il u re of o t he r s t o f i nd hi gh e r c a rd i o vas cu l ar
m o r ta li t y, 2 24 ha s d im in ish e d a n y ca r di o vas cu l a r co n ce r ns wi t h
P . 5 0 -7 0
s u lf o n ylu r ea s . O f no t e , th e U K P D S fo un d n o i nc re a se in th e ra t es of MI o r d ia b e te s - r e la t ed
d e a th s wh e n pa r t ic ip a nt s t r e at e d i nt e ns i vel y wi t h a su l fo n yl u re a we r e c omp a r ed wi t h th os e
t r e a te d c on ve n ti o na ll y. 22
Th u s , c u r re n t e vi de nc e in d ic a te s t ha t th e b e ne f its o f su l fo n yl ur e as fa r ou twe i g h t he i r r is ks in
t yp e 2 d ia b et ic pa t ie n ts wi t h c a rd i o vasc u la r di sea s e. O n th is ba si s, t he i r u s e is no t
c o nt r a in di ca t ed .
Lactic Acidosis
M . R . is a 7 6 - ye a r - o l d , 5′ 1 1 ″ , 1 50 - l b m a n ( B MI 20 . 9 k g / m 2 ) w i t h t yp e 2 di a b e te s w ho w a s
h o s p it a l iz ed w h e n h is so n f o un d hi m i n a “n e ar - u n c o ns c io u s s t at e .” Ac c o r d i n g t o h is
s o n , M . R .' s d i a be t es h ad b ee n ad e qu a t el y m a n a g e d w it h gl i p iz i de 10 m g B I D a n d a c a rb o se
1 0 0 m g T I D w i t h e ac h m e a l u n t il ap p r o xi m at e ly 2 m o n t h s a g o , w h e n M . R . w as ho s p i ta l iz ed
f o r p n eu m on i a . B e ca u se M . R. l i ve d a l on e a n d a d a ma n t l y r e f u s e d t o ta k e “ sh o t s, ” h e w as
d i s ch a r g ed o n m et f o r mi n , w h ic h w as t o b e a d de d t o h i s o t he r me d i ca ti o n s . A r e vi ew o f
t h e ho s p it a l re c o r ds r eve a l e d a n S r C r o f 1 .4 mg / d L a n d s e ve r a l r a n dom b l oo d gl u co s e
c o n ce n t r a ti o ns > 19 0 mg / d L . H e al s o h as a h i st o r y o f c h r o n i c o b s t ru ct i ve p u l mo n a r y
d i s ea s e ( C O P D ) . H i s c ur r e n t d os e o f me t f o r min i s 8 5 0 m g T I D w i th me a l s.
O n p h ys i c a l e x a mi n a ti on , t h e p a ti e n t w a s o r i en t e d , b u t a p pe a r ed ac ut e l y i l l . T em p e r at u r e ,
p u l se , an d B P w e re w i th i n no r m a l l im i t s. T he re s p i ra t o r y r a t e w as 32 b r e a t hs / mi n .
S i g n i f ic a nt l ab o r a to r y va l u e s in c lu d ed t he f o llow in g : N a , 14 0 m E q / L ; K , 6 . 2 m E q/ L
( n o r m al , 3. 5 to 5 ) ; C l , 10 3 m Eq / L ( n o r ma l , 9 5 to 1 05 ) ; H C O 3 , 5 m Eq / L (n o r m a l, 22 t o 2 8 ) ;
a r t e r i a l p H , 6 . 8 ( n o rm a l, 7 . 36 t o 7 .4 2 ) ; S r C r 3 . 2 m g / dL ( no r m a l, 0. 7 to 1 . 4 ) ; b l o od gl u c os e ,
1 3 0 m g /d L ; s e r u m a ce to n e s, n eg a t i ve ; s e r um la c t a te , 1 2 .3 mm o l /L ( n or m a l , 0 . 7 t o 2 . 0 ) ;
a n d s e r u m p yr u va t e , 0 .4 9 mm o l/ L ( no r m al , 0. 05 t o 0 . 08 ) .
A d i a g n o s is o f l ac t i c ac i d os i s w as ma d e. Wh at s i g ns an d s ym p t o m s a r e co n s is t e nt w i t h
t h i s di a gn o si s ? W h a t i s t h e r el a t io n be tw e en me t f o r m in an d la c t ic ac id o s is , an d w ha t a re
t h e p re d i sp o si n g fa c to r s ?
Th e m os t n o to r io u s si d e e f f ec t a ss oc ia t ed wi t h me t f o rm in — t ho ug h e xt r e me l y r a re — is la c ti c
a c id os is . L a ct ic ac id os is i s a m e ta b ol ic ac id os is c h a ra ct e ri ze d b y a si gn i fi c an t re d uc ti o n i n t he
a r t e ri a l p H a n d a n a cc um u la t io n o f s e ru m l ac ta te , a p r od uc t of an a er o bic me t ab ol is m . I t i s a
c o nd i ti on t ha t i s h ig h l y le t h al ( 50 % m or t al i t y) a nd r es is t an t to th e r ap y. La c ti c a ci do si s o cc u rs
wh e n t h e re is a n i nc r e ase d p ro du c ti on o f o r d ec re a se d u t il i za ti on o f l ac tat e . D ec r ea se d
u t i li za t io n o f l ac t at e o ccu r s wh e n t is su es a re una b le t o o xi d i ze la ct a te t o p yr u va t e ( t he se t wo
s u bs ta n ce s a r e n or ma l l y p r es e nt in th e s e ru m i n a r a ti o o f 1 0 :1 ) . Me t f o rm in mi g ht p re d is po se a
p a t ie n t t o l ac ti c a ci d os is b y a ug me n ti n g a na e r ob ic me t ab ol is m o r b y d ec re a si n g t he k i dn e y' s
a b il i t y to ha n dl e a n a ci d l o ad . O t he r fa ct o rs t ha t m i gh t c on t r ib u te t o la c ti c a ci d os is i nc l ud e
s e ve r e ca r d ia c o r p ul m on a r y d is ea se ( an o xi a , inc r e as ed la ct a te p ro d uc tio n ) , s ep t ic s h ock ,
r e n al d ysf u nc ti o n ( r e te n ti o n o f m e tf o rm in an d l ac ta t e ) , a nd e xc e ss i ve a lc oh o l i n ta ke (i n cr e as ed
l a ct a te p ro d uc ti o n a nd de c r ea se d u t il i za ti on ) .
S i g ns an d s ymp t om s g ene r a ll y a r e ac u te in on s et a n d c omm o nl y i nc lu d e na u se a , vo mi t in g ,
d i a r rh e a, an d h yp e r ve nt ila t i on . H yp o vol em ia , h ypo t e ns io n , co n fu si o n , a nd c om a a ls o m a y
o cc u r ; d ea t h i s us u al l y se c on d ar y t o c a rd i o vasc u la r co ll a ps e .
A s il lu s t ra t ed b y M. R . , t yp i ca l l ab o r at o r y fi n di n gs i n cl ud e a lo w s e r um bi car b o na t e a nd P C O 2 ; a
l o w a r t e ri a l p H ; a n e le va t e d p o ta ss iu m ; a n o rm a l o r lo w s e r um c h lo r id e ; e le va t e d l ac ta t e a n d
p yr u va t e l e ve ls ; a n i nc r ea s ed L: P r at i o; an d a n an i on ga p of ≥ 30 mE q /L .
Tr e a t m en t i s e mp i ri c a nd i nc l ud es th e fo ll o wi n g : co r r ec t io n o f an y u nd e rl yin g c a us e o f a n o xi a
a n d e li mi n at i on of f ac to rs p re d is po si ng t o l ac ti c a c id os is , l a r ge do se s o f s o di um bi ca r bo n at e
wi t h f r e qu e nt a rt e r ia l p H d e t e rm in a ti on s , h em od ial ys is , an d g lu co s e pl u s in s ul in in f us io n . Th e
l a t te r a re ad mi ni s te r ed in a n a t te mp t t o i mp r o ve t h e m e ta bo l ic u t il i za ti o n o f la c ta t e a nd
p yr u va t e . 1 3 8 , 2 25
A l t h ou gh me t fo r mi n ra r ely i s ass oc i at e d wi t h la c ti c ac id os is , th e m an u fa c tu r e r a n d t he F D A
h a ve ta k en e xt r e me m e as u r es to pr e ve nt i ts i mp ro p e r u se be ca us e a n ot he r bi g ua n id e ,
p h e nf o rm in , wh i ch in d uce d th is li f e -t h r ea t en in g co n di t io n wa s re mo ve d f ro m th e m ar k et in
1 9 7 7. 2 11 Th e e st im a te d r a t e o f p h en f o rm in - in d uce d la ct ic ac id os is wa s 0 .2 5 to f ou r c as es pe r
1 , 0 00 us e rs ve rs us fi ve to n in e c as es pe r 1 0 0, 0 00 us e rs f or me t fo r mi n . 2 20 , 2 26 , 22 7 A g r ou p o f
c l in ic ia ns f r om t h e F D A s um ma r i ze d 4 7 co n fi r med ca se s o f m e tf o rm in - r ela t e d l ac ti c a ci do si s
( l a ct a te le ve ls ≥ 5 mm o l/L ) t ha t h a d b ee n re p or t ed t o t h e F D A b e t we e n Ma y 1 9 95 an d J un e
1 9 9 6. 2 27 U nf o r tu n at e l y, t h e c on d it i on c o nt i nu es to b e r es is t an t to t re a tm en t in th a t t h e re wa s a
4 3 % m o rt a li t y r at e . I mp or t a n tl y, 43 o f t he 47 ca se s (9 1 %) ha d c o nc u rr e nt c on d it i on s t ha t
p r e di sp os e d t h em t o l ac ti c a ci d os is . Th es e i nc lu de d c a r di ac di se as e (6 4%) , d ec r ea se d re na l
f u nc t io n (2 8 %) , an d c h ron i c p ul mo n ar y d is ea s e (6 % ) . Se ve r al pa t ie n ts (17 % ) we r e o ver t he ag e
o f 80 ye a rs an d m a y h a ve h ad de c re as e d r en a l f un c ti o n d es pi t e n o rm al S rC r c on ce n t ra t io ns .
I n t e re st i ng l y, 3 8 % o f t h e p a ti e nt s h ad C H F , a n d th o se wh o di e d we r e mo re l ik el y t o b e u nd e r
t r e a tm en t wi t h d ig o xi n an d fu r os em i de . Th e m ean d ai l y do se of me t fo r min wa s we l l wi t h in th e
t h e r ap eu t ic ra n ge an d wa s n o t h ig h e r i n t he g ro up t ha t s uc cu mb e d ( 1 ,2 5 9 ± 6 48 mg in th e
g r o up t ha t d i ed an d 1 , 349 ± 59 8 m g i n t h e g r ou p t h a t s ur vi ve d ) .
A s a c on se q ue nc e o f t h is an a l ys is , th e m an u fa c tu r e r h as ch a ng ed i ts l a be l in g to wa r n ag ai ns t
t h e u se o f me t f or mi n i n in d i vid u al s wh o a r e b ei n g t r e at e d f o r C H F . Fu r t he rm o r e, m e t f o r mi n
s h ou l d n ot be in i ti a te d i n p a ti e nt s o ve r 80 ye ar s ol d un le ss a C l C r e va lu a tio n c o nf i rm s n o rm al
r e n al f un ct i on . Th e d r ug s h ou l d n ot be us ed wh e n p a ti e nt s a r e i n se p si s. 13 6
U n f o r tu n at e l y, s tu d ie s ass es si n g t h e a pp r op r ia t e u s e o f m et f o rm in ( acc o r di n g t o t h e
m a nu f ac tu r e r ' s r ec om men d a ti on s ) r e ve al th a t m etf o r mi n i s f r eq u en t l y u se d i n p a ti e nt s i n wh o m
i t is c o nt r ai n di ca t ed . 22 8 , 2 2 9 , 2 3 0 , 2 31 A re t r os pe cti ve co h o rt st u d y o f 1 , 8 47 p a ti e nt s f o un d t h at
2 4 . 5% of pa t ie n ts wh o r ec e i ved m e t fo r mi n h ad con d i ti on s f o r wh ic h i t wa s c o nt r a in di ca t ed
( 2 1 . 0% ha d C HF an d we re r ec e i vin g l oo p d i u re t ics , an d 4 . 8% ha d re na l i mp a i rm en t ) . 2 2 8
Me d i c a r e p a ti en t s h os pi ta l i zed wi t h th e p r im a r y di a gn o si s o f h ea r t f a il u re a n d c on co mi t an t
d i ab e te s we r e a ss es se d f o r m e t fo r mi n a nd TZ D us e , b o th of wh i ch a re con t r ai n di ca t ed in t hi s
s i tu a ti o n. 2 31 B et we e n 19 9 8 a n d 1 99 9 , 7 .1 % a n d 7 . 2 % o f p a ti en t s we r e t re a t ed wi t h m e tf o rm i n
a n d a TZ D , r es pe ct i ve l y, a t di sc ha r ge ; th es e n umb e r s i nc re a se d b e t we e n 2 0 0 0 a nd 20 01 t o
1 1 . 2% an d 1 6 .1 % . I n p a ti e n ts wi t h r e na l d ys f un ct io n ( S r C r 1 . 5 mg / dL o r h ig h e r ), me t fo r mi n wa s
u s ed in 9. 3 % a nd 15 . 2% o f pa t ie n ts in 19 98 – 19 9 9 a n d 2 00 0 –2 00 1 , r e sp ec ti ve l y. S ee Q u es ti o n
6 5 fo r di sc us si on o f TZ D s an d h e a rt f ai lu r e . C l in ic i an s n ee d t o c a re f ul l y as se ss pa t ie n ts fo r
c o nt r a in di ca t io ns be f o re i n i ti a ti ng o ra l a g en ts .
P . 5 0 -7 1
M. R . ' s p u l mo n ar y d is e ase ma y h a ve c au se d a n an o xi c s ta t e, wh i ch p re d isp o se d h im to la c ti c
a c id os is . Fu r th e rm o r e, eve n t ho u gh hi s S r C r wa s < 1 .5 mg / dL , th is va lu e m a y no t ha ve r ef l ec te d
n o r ma l r e na l f u nc ti o n i n t h is el d e rl y g en t le ma n . 23 2 Fi n al l y, d e h yd ra ti o n ca u se d b y e xt e n s i ve
vo m i ti n g a nd di a r rh e a h a s ca us e d p re r e na l f a il u re t h a t is li ke l y c o nt r i bu t ing t o t h e ac i do si s.
C l i ni c al N ot e : M. R . r e c o ve r e d f o ll o wi n g a gg r es si ve t r ea tm e nt wi t h fl u id s an d s o di um
b i ca r bo n at e . Me t f o rm in wa s d i sc on t in ue d a n d h e wa s m an a ge d wi t h i ns uli n .
Hypoglycemia
C . A. , a 6 8 - ye a r - o l d w om a n w ho h as ha d a 20 -ye a r h i s t o r y o f t yp e 2 di a b e te s a n d a 5 - ye a r
h i s t o r y o f m i l d r e na l fa il u r e ( S r C r , 1 . 5 m g /d L ; B U N , 3 0 m g / dL ) , is ad mi t t e d to t he h os p i ta l
i n a c o ma . Ac c o r di n g to h e r d a u gh t e r , C . A. ' s d i a be t e s h as b ee n w el l c o n t r o ll e d o ve r t h e
p a s t s e ve r a l m on t h s w it h g l yb u r i d e 1 0 mg B I D . S h e to o k h e r la s t d o se a p p r ox i ma t e l y 5
h o u r s b e f o re a dm i ss i on . T h re e da ys b e f o r e ad m i ss i o n C . A. d e ve l o ped a n o re x ia , na u se a ,
a n d vo m it i n g i n a s so c ia t i o n w it h t he f lu an d be c a me p ro g r e ss i ve l y l e t h a r g ic . La b o r at o r y
r e s u l ts o n a dm i ss i o n ar e a s f o l low s : p l a sm a gl u c os e , 2 0 m g /d L ( no r ma l , 70 t o 1 40 ) ; S r C r ,
3 . 0 m g / dL ( no r m a l, 0. 6 t o 1 .2 ) ; a n d B U N , 8 0 mg / d L (n o r ma l , 7 t o 2 0 ). W h a t i s C . A. ' s
d i a g no s is ? We r e th e r e a n y p r e d i s p os i n g f a ct or s ?
[ S I un i ts : S r C r, 13 2 .6 and 2 6 5 . 2 µ m ol / L; B U N , 1 0. 7 an d 2 8 .6 mm ol / L; pl asm a g l uc os e, 1 .1
m mo l /L ]
C . A . h as d e ve lo p ed a cas e o f s e ve r e h yp og l yce mi a s ec o nd a r y to gl yb u r ide . H yp o gl yc em ia is
t h e m os t c om mo n ( i nc id en c e, 2 .4 of 10 0 p a ti e nt s p e r ye ar ) an d p o te n ti a ll y s e ve re ( 4% to 7%
m o r ta li t y ) a d ve rs e e ff e ct o f th e s ul f on yl u re a s. The i nc id en c e a nd s e ve r it y o f t hi s e ff ec t
i n c re as e wi t h t he du r a ti on o f a ct i on an d p o te nc y o f t he ag en t s. Th u s, th e i n ci de n ce of s e ve r e,
p r o lo n ge d h yp o gl yc em ia s ec o nd a r y to ch lo r p r op am i de an d g l yb ur i de is a pp r o xi m a t el y t wo t im es
h i gh e r th an t ha t f o r g l ip izi d e an d a p pr o xi m a t el y fi ve t im es hi gh e r t h an th at f o r
t o l bu t am id e . 1 4 5 , 1 46 , 23 3 A s di sc us se d i n t h e se c tio n on d ru g -i n du ce d h yp og l yc em ia la t e r i n
t h is ch ap t e r, t he s u lf o n ylu r e as acc o un t fo r alm o st a l l ca se s o f d r u g - i nd uc ed h yp og l yce mi a i n
i n di vi d ua ls ol d er t ha n a ge 6 0.
Mo s t s u lf o n ylu r ea - i nd uce d h ypo g l yc em i a oc cu r s i n pa t ie n ts wh o a r e p r e dis p os ed t o
h yp o g l yc em i a i n so me wa y, a nd C . A . i s n o e xc e pt i o n. S he is a n e l de r l y wo m an wi t h re n al
i m pa i rm en t wh o wa s on re l a ti ve l y hi gh do s es o f an a ge n t, a p o rt i on of wh i c h i s e xc r e t e d
u n ch a ng ed in t he ur i ne . E ve n i n t he f ac e o f d ec re a se d c a rb o h ydr a t e in t ak e (a n or e xi a a nd
vo m i ti n g ), s h e c on ti n ue d t o ta ke he r us ua l d os e of g l ybu r i de . E ven th o ug h t h e s t re ss o f il ln es s
m os t of t en r ai se s g lu co se l e vel s, t he de c re as ed in t ak e a n d vo m it in g p r o ba b l y le d t o
d e h yd ra t io n a n d f u r th e r c om p r om is ed r en al f un cti o n .
B e c au se gl yb u ri d e a nd ch l o rp r o pa mi de ha ve a l on g du r a ti on o f ac t io n , h yp o gl yc em i a i nd uc ed
b y t h es e a g en ts m a y l as t f o r s e ve ra l h o u rs , o r d ays i n t h e ca se o f ch l or p ro p am i de . Th e re f or e ,
p a t ie n ts s uc h a s C . A . mu s t b e h os pi t al i ze d a nd tr e a t ed wi t h c on t in u ou s gl u co se in f us io ns un t il
o r a l i nt a ke re su m es . O t h e r wi s e , s e ve re h ypo g l yce m ia m a y r ec u r.
Use of Oral Antidiabetic Agents in Special Situations
Renal Dysfunction
G l yb u r i d e w a s w i t h he l d a n d C. A. ' s k i dn e y f u n c t i o n st a b il iz e d w it h f lu id r e p la c em e nt ( C l C r
= 3 5 m L /m i n ). B ec a us e s h e li ve s al o ne , ha s i mp a i r e d e ye s i g h t s e co n da r y t o c a t a r a c ts ,
a n d ha s s e ve r e a r t h r i t is , i ns u l in t r ea t me n t is im p r a c ti c al . O r a l a ge n t s a r e t o b e
c o n t in u e d. W hi c h a ge n ts s ho u l d b e a vo i d ed ? W h i c h a ge n t s c ou l d b e u s e d?
[ S I un i t : C l C r , 5. 8 3 m L/ sec ]
O n c e C .A . ' s p la sm a g l uco s e co n ce n tr a ti o ns a n d re n al f un ct i on ha ve st a bi li ze d , re i ns ti t ut i on of
a n t id ia b et ic t he r ap y m ust b e c on si de r e d. S ul f on ylu r e a c om po u nd s t ha t a r e m e ta bo l i zed to
a c ti ve p ro d uc ts th a t d epe n d o n t h e ki d ne y f o r e lim i na t io n ( e . g. , a ce t oh e xa m id e ,
c h lo r p ro p am id e g l ybu r i de , an d to la za mi d e ) sh o uld b e a vo id e d i n t he el d erl y a n d i n p at i en ts
wi t h d ec r e as ed r en al f unc t io n . S u lf o n ylu r ea s t h at a r e c om pl e te l y me t ab ol ize d t o i na c ti ve o r
we a k l y a ct i ve p r o du ct s m a y be us e d ( i .e . , g li pi zid e , g l im ep e ri d e, o r t ol b ut a mi d e ). A lt h ou gh
g l yb u ri d e is un l ik el y t o ac cu m ul at e i n p a ti e nt s wi th a Cl C r >3 0 m L/ m i nu t e, i t s h ou ld no t be
u s ed in C . A . b ec au se in h e r , i t c au se d a se ve r e hyp o g l yce mi c r e ac ti o n. F ur t h e rm o re , e ven
p a t ie n ts wh o ar e n o t t ak in g s u lf o n yl u r ea s a r e m ore l ik el y t o e xp e r i e nc e h yp o gl yc em ic r ea ct i on s
i f th e y h a ve r e na l i ns u ff ic i en c y; t h e re f or e , a n y o ra l h ypo gl yc em ic ag e nt sh o ul d b e i n it i at e d a t a
l o w d o se an d ti t ra t ed sl owl y ( Ta b l e 5 0 -3 3 ) . C. A . sh o ul d b e i n st r uc t ed to eat r e gu l ar l y, be ca us e
s ki p pe d m ea ls ma y r es ult i n r ec u r re n t h yp o gl yc em i a. 1 47 , 23 4
Me t f o r m i n is co n t ra in d ica t e d i n C . A . b ec a us e h e r r e n al fu nc t io n i s a bn o rma l (s e e Q u es t io n 6 6 ) .
D e c r ea se d re n al fu nc t ion ca n re su l t i n a cc um ul at i o n o f m et f o rm in , wh ic h c a n, in t ur n ,
p r e di sp os e h e r to l a ct ic a c id os is .
Th e TZ D s a r e p ri m ar i l y m e ta b ol i ze d b y th e l i ve r a n d a r e n o t co n t ra i nd ic at e d i n p a ti e nt s wi t h
m i ld re n al fa i lu r e . Th e us e o f ro si g li t a zon e o r pi og l i ta zo ne , be gi n ni n g wi t h l o w d os e s, c o ul d b e
c o ns id e re d a s c an ac a rbo s e, wh i c h is po o rl y a bso r b ed f ro m t h e G I t ra c t. N o n e o f th es e a g en ts
c a us e h yp og l yce mi a wh en us e d a s mo n ot h er a p y.
Hepatic Dysfunction
B . R . , a 6 0 - ye a r - o l d m a n w i th c i r rh o s is o f t h e l ive r , i s f ou n d to ha ve t yp e 2 d i ab e t es .
G l i p i zi d e 1 0 m g Q D is in i t i a te d . How w i l l B. R . 's l i ve r f un c t io n af f e ct th e d is p os i t io n o f
g l i p iz i de an d hi s r es p on s e to t h is ag e n t?
B e c au se he p at ic me t ab ol i sm i s t h e p ri ma r y r o ut e o f el im i na t io n f o r m os t su l f on yl u re as ,
i n cl ud i ng gl i pi zi de , p a ti en t s wi t h h ep a ti c d is ea se s h ou l d b e e xp e c te d to ha ve a n e xa g g e r at e d
r e s po ns e t o th os e d r ug s m e ta b ol i ze d t o l ess ac t i ve p r od uc ts .
To l b u t am id e i s t he su l fon yl u r ea t ha t h as be e n s tu d ie d m os t e xt e n s i ve l y wi t h r e sp ec t to li ve r
d i se as e . I n a do u bl e -b li nd , pl ac e bo - co n t ro ll e d t r ia l of 50 ci r r ho t ic p a ti e nts , h ypo gl yc em i a wa s a
c om p li ca t io n i n 2 0% o f th e to l bu t am id e - tr e at e d gr o u p . 2 35 To l bu t am id e ' s e l im in a ti o n h al f -l i fe in
s u bj ec ts wi t h c i r rh o si s ha s b e en r ep o r te d t o b e in c r ea se d o r un al t e re d i n d i ff e r en t s t ud ie s . 2 3 6
A c om pl ic a ti n g f ac t or is th a t a lc o ho l c an in d uc e he p a ti c e n zym es , ma r ke d ly i n c re as i ng
t o l bu t am id e m et a bo li sm in a lc oh ol ic p at ie n ts wi t h c i r rh os is .
L i ve r di se as e c an be a se p a ra t e p r ed is p os in g f act o r fo r s e ve r e, p ro l on ge d h yp o gl yc em ia
b e ca us e g l yco g en o l ys is a n d g lu c on eo g en es is a re i mp a ir e d; t hu s, su l fo n ylu r e as ar e re l at i ve l y
c o nt r a in di ca t ed f or ci r r ho t ic pa t ie n ts . I f th e y a re u s ed , s h or t e r -a ct i ng ag en t s a r e p r ef e r re d a n d
s ma l l i ni ti a l d os es s h ou ld b e us e d. F or B . R . , g li pi zi d e c ou ld b e in i ti a te d at a do se no g re a te r
t h a n 2 .5 mg / da y a nd in c re a se d i f n e ed e d b y 2 .5 -m g i nc r em e nt s
P . 5 0 -7 2
a t no le ss th a n we e k l y i nt e r va ls . An o th e r o p ti o n is lo w d o s es o f re p ag li n ide ( 0 .5 m g ) o r
n a t eg li n id e (6 0 m g ) wi t h m e al s.
Table 50-33 Treating Type 2 Diabetes Under Special Circumstances
Circumstance
Patients with decreased
renal function
Avoid
Consider
Acarbosea
Glipizide
Acetohexamide
Glimepiride
Chlorpropamide
Tolazamide or tolbutamide
Glyburide
Insulin
Metformin
Repaglinide/nateglinide
Thiazolidinediones
Patients with impaired liver
function
Acarbosea
Insulin
Acetohexamide
Repaglinideb
Chlorpropamide
Miglitol
Metformin
Thiazolidinediones
? Glyburide
Patients who are obese or
gaining excessive weight
Insulinc
Acarbose
Sulfonylureas
Miglitol
Repaglinide
Metformin
? Thiazolidinedionesd
Patients experiencing
hypoglycemia due to
irregular eating patterns
Insulin
Acarbose
Long-acting
sulfonylureas
Metformin
Repaglinide/nateglinide
Thiazolidinediones
a
This is a labeled recommendation. Although very little acarbose is absorbed into the
systemic circulation, the small amount available relies on the kidneys for elimination. This
accumulation and doses ≥300 mg daily rarely have been associated with elevated liver
enzymes. Plasma concentrations of miglitol in renally impaired volunteers were
proportionally increased relative to the degree of renal dysfunction.
b
The manufacturer recommends more cautious dose titration in these cases.
c
This recommendation presumes that the patient can be controlled on oral agents. Often by
the time insulin is required in type 2 diabetes, pancreatic function may have deteriorated
considerably.
d
Rosiglitazone is associated with mild weight gain (1.2 to 3.5 kg) and pioglitazone has been
associated with mild to moderate weight gain (2 to 8 kg).
Diabetes in the Elderly
Clinical Presentation
J . M . i s a f ra i l , 8 2 - ye a r - o l d , u n r e sp o ns i ve ma n , w ho i s b r o ug h t to t he E D . Ac c o r d i n g t o
J . M .' s fa m il y, h e h a s b ec o m e i nc r e as i n gl y c o n f u s e d, d iz z y, a n d l e t ha rg i c , w i th a r e ce n t
w e ig h t lo s s o f 1 0 l b . J .M . li ve s b y h i m s e l f an d h a s b e en ge n e ra l l y h e a l t h y w i t h th e
e x c ep t i on o f m i ld t o mo d e r a te C O P D a nd a r thr i t i s . F a s ti n g s e r um che m i s t r y r e ve a l s t h e
f o l l ow i ng : N a , 12 8 m E q/ L ( n o rm a l, 13 5 to 1 45 ) ; g l u co s e, 79 8 m g / dL ( no r m a l , 7 0 t o 1 0 0 ) ;
a n d s e r u m o sm o la l i t y, 3 7 4 m O s m /L ( no r m al , 28 0 t o 2 95 m O sm / kg H 2 O) . H i s s e r um is
n e g a ti ve f o r ke t o ne s . O n p h ys i c a l e x am i na t i on, J .M . ha s p o o r s k in t u rg o r a nd d r y m u c o u s
m e m b ra n es an d is r es po n s i ve on l y t o d e e p p ain . H i s B P i s 9 0/ 6 0 m m H g w it h a p u ls e o f 96
b e a t s/ m in . H e i s n o te d t o h a ve r al e s a t t h e l e f t l ow e r ba s e o f h i s l u n g, a n d a ch e s t
r a d i o g ra p h c o n fi r m s p ne u m on i a . D e sp i t e a g g res s i ve f lu i d re p l ac em e n t, J .M . 's b lo o d
g l u c os e re m ai n s c o ns is t e n t l y > 2 5 0 m g/ d L a n d h i s A 1 C i s 1 1 % ( n o r m a l, ≤ 6 %) . J . M . p r e se n t s
w i t h ve r y h i g h g l u co s e c o n ce n t r a ti o ns , bu t has n o h i s to r y o f d i a b e tes m el l i t us . W h a t
s p e ci a l f a c to r s c o n t r ibu t e t o a la t e a n d a t yp i c a l p r es e n ta t i on o f d i abe t e s i n th e e l d e rl y?
[ S I un i ts : Na , 12 8 mm o l/L ( n or ma l , 1 35 t o 1 4 5 ) ; gl u co se , 4 4 .3 an d >1 3 .9 m mo l /L ( no r ma l , 3 .9 to
6 . 1 ) ; se r um os mo la l it y, 37 4 m mo l /k g ; A 1 C , 0 . 11 ]
D i a b et es in th e e l de r l y co mm o nl y is un d e rd ia g nos e d a nd un d e rt r ea t ed bec a us e i t o f te n
p r e se n ts a t yp ic al l y. 23 7 , 23 8 , 23 9 Cl as si c s ymp t oms as so ci a te d wi t h d ia b ete s m el l it us ma y b e
m as k ed b y o t he r il ln es ses , m a y be en t i re l y ab se nt , o r m a y b e e xp l a i n ed awa y b y t h e n o rm al
a g in g p r oc es s . F o r e xa m p l e , p ol yu r ia is m in im i zed b y h i g he r re n al th r es ho l ds fo r gl uc os e o r
m a y be co n fo u nd ed b y ur i n a r y i nc o nt i ne nc e o r “ pr o s ta t e p r ob le ms . ” Th i rs t i s c omm o nl y b lu n te d
i n el de r l y pe r so ns , i nc r ea s in g t h ei r ri sk of de h yd ra t i on an d e le c t ro l yt e im ba l an c e. H un g e r ca n
b e al t e re d b y me d ic at i ons o r d ep r es si o n. Fa t ig u e o f t en is di sc ou n te d a s “ pa r t of ge t t in g o ld , ”
a n d we i gh t l os s , t ho u gh s om e ti me s p r o fo un d , m ay b e so g ra du a l t ha t it go e s u nn o ti ce d f o r
m o nt hs t o ye a rs . ( Se e Ta b le 50 - 3 4 f o r a c om p ar is o n o f p r es en t in g s ym pto ms f or di a be t es
m e ll i tu s i n e ld e rl y p at i ent s c om p a re d wi t h yo u ng er p a ti e nt s. )
Hyperosmolar Hyperglycemic State
J . M . i s d i ag n os e d w it h h yp e r o s m o l a r h yp e r g l yc e m ic s ta t e ( H H S ) . Wh y a r e t he el d e r l y
p r e d i sp o se d to t h is con d i t i on an d w h at s ig n s a n d s ym p t o m s a re c ons i s t en t w i t h t h is
d i a g no s is ?
H H S i s a c o nd i ti o n ch a rac t e ri ze d b y e xt r e m el y e le va t e d p la sm a g lu co se co n ce n t ra t io ns ( >6 0 0
m g /m L ) a nd hi g h se r um o sm o la li t y ( > 33 0 m O sm /L ) wi t h o ut ke t oa ci do si s . B e c au se pa t ie n ts wi t h
t yp e 2 d ia b et es h a ve som e re si d ua l i ns ul i n p r odu c ti o n,
P . 5 0 -7 3
t h e y a re us ua l l y p r o te ct ed a ga in s t e xc e ss i ve l i po lys i s a nd ke t on e p r od u ct io n . Me a su r em e nt s o f
s e r um k e to ne s a n d bl o od p H d i f fe r en t ia t e t hi s c on d i ti on f ro m D K A ( se e Qu e st i on 40 ) . Th e
c o nd i ti on oc cu r s wh e n u ri n a r y fl ui d a n d e le c tr o l yte l oss es se co n da r y t o g lu c os u ri a a r e
i n ad e qu a te l y r ep l ac ed by o r a l f l ui d i n ta ke . 92 , 24 0
Table 50-34 Presentation of Diabetes Mellitus in Elderly Patients Compared With Younger
Patients
Metabolic Abnormality
Symptoms in Young
Patients
Symptoms in Elderly Patients
Serum osmolality
Polydipsia
Dehydration, confusion,
delirium
Glycosuria
Polyuria
Incontinence
Catabolic state due to insulin
deficiency
Polyphagia
Weight loss, anorexia
H H S p r im a ri l y oc cu r s i n th e el de r l y be ca u se s e ver a l s i tu a ti on s p r ed is p os e t h is po pu l at i on to
h yp o d ip si a . Th e se in cl u de a n i na bi l it y t o re co g ni ze t hi r st , 24 1 a n i n ab il i t y to as k f o r f l ui ds ( e. g .,
d e me n ti a , se d at i on , i n tub a t io n ) , a nd an in ab i li t y t o ge t fl ui d s o n d em an d (e . g . , p h ys ic a l
d i sa bi l it i es o r r es t ra i nt s ). I n fe ct i on s o r o t he r ac u te i ll ne ss es ( e. g ., MI , G I b l ee d in g ,
p a nc r ea t i ti s) t ha t e xa c e rb a t e d ia b et es c a n i nt e r ac t wi t h t h e h yp e ro sm ol a r d i ur e si s a nd
h yp o d ip si a t o p r od u ce se ve r e de h yd ra t io n a n d hyp e r g l yce mi a . D r u gs th a t i nc r e as e p la sm a
g l uc os e c on ce n t ra t i o ns (e . g . , gl u co co r ti c oi ds ) , i nc r e as e d iu r es is , o r de c rea s e me n ta t io n a ls o
c a n co n t ri b ut e to th is un fo r t u na t e si t ua t io n .
J . M. p r e se n ts wi t h s e ve ra l s ym p to ms o f H H S d e hyd r a t i on , i nc l ud in g o sm ola l i t y > 3 20 m O s m,
p l as ma gl uc os e > 6 00 mg/ d L , d ec r ea se d s ki n t u r go r , h ypo t en si o n, an d th e a bs e nc e o f s e ru m
k e to n es . Hi s p ne um o ni a wa s p r o ba b l y t h e p r ec ip it a t in g f a ct o r . Th e m o r ta l it y r a t e f o r t h is
d i so r de r is 3 % i n p a ti e nts yo un g e r t ha n 5 0 ye ar s o f ag e ; i t i nc r ea se s t o 3 0% f o r t ho se ol d e r
t h a n 5 0. 2 42 Tr e a tm en t in vo l ve s r a pi d I V h yd ra t ion , r ep l ac in g h al f of th e wa t e r d e fi ci t i n th e
f i r st 5 h ou r s u si ng 1 L / ho u r of no r ma l s al in e . The a dm in is t r at i on ra t e i s th e n re du ce d to 25 0 t o
5 0 0 m L/ h ou r un t il ad eq ua t e h yd r a ti o n h as b e en es t ab l is he d . 9 2 , 2 4 0 I ns ul i n m a y be gi ve n
s im u lt a ne o us l y, i f i nd ic a te d , to c o r re c t t he h ype r gl yc em i a mo r e ra pi d l y. Reh yd r a t io n h as be e n
s u f fi ci en t to c o r r ec t J . M. ' s me t ab ol ic im ba l an ce , al l o wi n g h is d i ab e te s c on tr o l t o be ad d re ss e d
n o w.
Goals of Therapy
W h a t a r e th e go a ls o f th e r a p y f o r J . M . ?
I t is wi d e l y re co g ni ze d t ha t st r ic t g l yce mi c c on t r ol i s a ss oc ia t ed wi t h a n i nc r e as ed in ci de n ce of
h yp o g l yc em i a. 2 1 I n t h e e l de r l y pa t ie n t wi t h a ge - re l a te d a u to n om ic d ys f unc t io n , h yp og l yc em ia
m a y p re se n t wi t ho u t t he u s ua l p r em on i to r y s ymp to ms an d c a n r es ul t in s eve r e a d ve rs e e ff e ct s
s uc h a s a n gi na , s e i zur e s, s t ro ke , o r MI . Th e r e f o re , t he ge ne r a l t en d en c y wh e n t r e at i ng el de r l y
d i ab e ti c p a ti en t s is t o a im f or sl ig h tl y m or e l i be r al o ut co me ob j ec ti ve s .
Th e b as ic p ri nc i pl es of m a na g em en t a r e t o m ai nt a i n J . M. ' s fa s ti n g bl o od g l uc os e b e t we e n 1 00
a n d 1 4 0 mg / dL wi t h po stp r a nd i al gl uc os e val u es < 1 8 0 mg / dL , wh i le a voi d in g h ypo g l yc em i a. A n
A 1 C g oa l o f 8 % wo u ld be a p p ro p r ia t e i n t hi s f r ai l pa t i en t . 2 4 3
Diet and Exercise
H ow s h o ul d di e t a n d e xe r c i se r e co mm e n da t i ons b e m o di f i ed f o r e l de r ly d i a b e t i c pa t i en t s
s u c h a s J .M . ?
Nutrition
B e c au se m o st el d er l y pat i e nt s h a ve t yp e 2 di a be te s , n u tr i ti o n a nd e xe r c ise p r og r am s a re t he
i n i ti al st e ps i n t h e ra p y. In 2 00 1 , t he p re va l en ce of o be si t y i n t he U ni t ed S ta t es wa s 20 . 9% . 24 4
E l d e rl y p e rs on s b et we e n t h e a ge s o f 6 0 a n d 6 9 ha d a 2 5. 3 % p r e val en c e of o be si t y a nd pe o pl e
a t 70 an d o l de r ha d a p re va l e nc e o f 1 7. 1 %. O l der p e op le wi t h di ab e te s , es p ec ia ll y t h os e i n a
l o ng - t e rm c a re f ac il it y, ha ve a te nd e nc y t o b e u nd e r we i g ht r a th e r t ha n o ve r we i g h t . 3 6
Th e r e f o re , c a ut i on s h ou ld b e us e d wh e n co ns i de ri n g a we i g ht lo ss d i et , s in c e t hi s c ou ld ca us e
m a ln u t ri ti o n o r d e h yd ra t io n . Th e u se of ca lo r ie - r es t r ic te d d i et s i n t h e e ld er l y m us t e ns u re t ha t
t h e e xt e n t o f we ig h t l os s i s l im it e d a nd th a t m os t we i g h t lo ss pr im a ri l y com es f ro m a di p os e o r
f a t s t o re s, no t f ro m p r ot ei n or mu sc le st o re s . W eig h t re d uc ti o n is r ec omme n d ed i n el de r l y
p e r so ns o ve r t he ag e o f 7 0 on l y if t he pa t ie n t is ≥2 0 % o ve r we i g h t.
S e ve r a l f ac t o rs c an ad ve r s e l y a f fe c t p r op e r n ut r i tio n in th e e l de r l y. Th e y i nc l ud e a n i mp ai r e d
a b il i t y to sh op f or an d p re p a re f oo d , l imi t ed f in anc es , an ag e - re l at e d d ec lin e in ta s te
p e r ce p ti on s , a nd c o e xi s tin g il ln es se s . I ll - f it t in g d en t u r es , d if f ic ul t y i n ch e wi n g a nd s wa l lo wi n g ,
a n d l ac k o f c om pa n io ns hi p du r in g m ea ls al so ca n c on t r ib u te to ma ln u t ri t ion .
A d ec r e as e i n t he p ro p ort i o n o f s at u ra t ed f at t o <1 0 % o f c al o r ie s, as re com me n de d i n t h e A D A
m e di ca l n u t ri ti o n t he r a p y, m a y n o t b e a pp r o pr i at e i f m al n ut r i ti o n is p re se nt . O t h er
c o ns id e ra t io ns in cl u de ind i vi du a l f oo d p r e fe r e nc es , et h ni c b ack g r ou nd , and p h ys ic a l a nd
f u nc t io n al li mi t at i on s t hat m a y a f fe c t a dh e re n ce to sp ec i fi c d ie t a r y ad vi ce .
H i g h - fi be r di e ts m a y lo we r bl o od gl uc os e a n d imp r o ve pl as ma li pi ds . H owe ve r , h i g h -f i be r d i et s
i n f ra il , el de r l y pa t ie n ts , p a r ti c ul a rl y t ho se wh o a re b ed r id d en , s ho u ld be us e d ca u ti o us l y
b e ca us e th e y c a n b e co ns t ip a ti n g a nd r es ul t i n f ec a l im p ac ti o n. A mb ul a to ry p a t ie n ts , o n th e
o t h e r h an d , g en e ra l l y b en e f it f ro m i nc r ea se d d i eta r y f i be r . Be ca us e m an y e l de r l y pa t ie n ts ar e
m a ln o ur is h ed , a da i l y mu l t ip le - vi t am in p re pa r a ti on co n ta i ni n g t he r ec omme n d ed da il y
a l lo wa n c e o f e ac h vi ta min sh o ul d b e p r es c ri be d . A d e qu a te ca lc i um i n ta ke ( a t l e as t 1 , 20 0 m g
d a il y) s ho ul d b e a ss es sed a nd s u pp l em en t ed if r eq u i re d . 3 6
Exercise
E xe r c i s e i n t h e e ld e rl y pr o vi d es al l t h e b en e fi ts de r i ve d b y yo u ng e r i nd i vid u al s . I t i nc r ea s es
we l l - b e in g a n d gl u co se st a b il i t y a n d ma y d ec r ea se a p r o pe ns i t y to fa ll . E xe r c is e a ls o im p ro ve s
B P , t he li p id pr o fi l e, h ype r c oa gu l ab il i t y, a n d b one d en si t y. Fo r pa t ie n ts wi t h a r t h ri ti s , a qu a ti c
e xe r c i s e ma y b e s ub st i tut e d . B e fo r e s uc h a n e xe r c is e p r o gr a m is in i ti a te d , c a re f ul e val u at i on is
m a nd a to r y t o a vo id m yoca r d ia l i sc he mi a o r th e a cc e le r a ti on o f r e ti no p at h y. 1 0 1
Selecting an Oral Antidiabetic Agent in the Elderly
W h y i s i t i mp o r t a nt t o in s t i t u te d ru g t he r a p y t o t r e a t J .M . 's d ia b et e s? W h a t
c o n si d e r at i o ns sh o u ld b e ma d e i n s e le c t in g an i n i ti a l t r e a tm e n t r e g im e n ?
A s in al l p a ti e nt s wi t h dia b e te s me l li t us , p oo r gl yc em ic co n t ro l i nc r ea se s th e ri sk of lo n g -t e rm
c om p li ca t io ns . Al t ho u gh i t is te mp t in g t o m in im i ze t he im po r t an ce o f gl yce m ic c on t r ol be ca us e
t h es e c om pl ic a ti o ns ta ke s o l on g to de ve lo p , p a tie n ts su ch as J . M. m a y ha ve h ad un r ec o gn i zed
h yp e r gl yc em i a f o r ma n y ye a r s b e fo r e c li ni c al d i ag n os is . Th us , m an y h a ve a l re a d y be gu n to
d e ve l op c om p li ca t io ns . Fu r t h er mo r e , a s li f e e xp e ct a nc y i nc r ea se s o n e ca n e xp e c t t ha t th es e
i n di vi d ua ls wi l l l i ve l on g e n o ug h t o e xp e r i e nc e mo r b id i t y re l at e d t o d ia b ete s i f th e y a re no t
t r e a te d . Th e r e fo r e , p ha rm ac o lo g ic t r e at me n t s hou l d b e s t ro n gl y co ns i de re d in J . M. a n d m os t
e l de r l y pa t ie n ts wh e t he r o r n ot th e y a re s ym p to ma t ic . 24 5
Th e g e ne r al ap p r oa ch to t r e at i ng an el d er l y pa t ien t wi t h t ype 2 d ia b et es is ba si ca l l y th e s am e
a s d es c ri b ed in Q u es ti o ns 50 an d 5 2 . Th e i ni t ia l ch o ic e o f a n a n ti d ia b et ic a g e nt s h ou l d b e
b a se d o n t h e s e ver i t y of h yp e r gl yc em i a. O t he r c on s id e ra t io ns in cl u de bo dy we i g h t , c o e xi s t i n g
d i se as es , an d c os t o f t he a ge n t. P a ti en t s
P . 5 0 -7 4
wi t h I F G ( F P G >1 0 0, bu t < 1 26 mg / dL ) s h ou ld be tr e a t ed wi t h d i et an d e xe r c is e ta il o r ed to th e i r
i n di vi d ua l c ap a bi li t ie s. Fo r p at i en ts wi t h di ab e te s ( F P G ≥ 1 26 m g /d L or 2 -ho u r po st p r an di a l
b l oo d g l uc os e > 2 00 m g /dL ) , ac a rb os e , n at e gl i ni de o r r ep ag l in id e , o r a TZ D a r e a ll ap p r op r ia t e
o p t io ns . Su l fo n yl ur e a -i ndu c ed h ypo g l yc em i a is a c o nc e rn in th es e p a ti e nts . H o we ve r , i f
i n ab i li t y t o a dh e re to t he m ul t ip l e - d ai l y r eg im en is p ro b le ma t ic , a s ul f o n ylu r e a wo ul d b e an
a p p ro p r ia t e a lt e rn a ti ve ag e n t. I n J. M. ' s c a se , m etf o r mi n s ho u ld pr o ba b l y be a vo id e d b ec au se
h e ha s C O P D . A ls o , h e is ol d e r t ha n a g e 8 0 a nd r e q ui r es a C l C r t o a ss es s h is ki dn e y f un ct i on ,
b e ca us e re n al fu nc t io n ca l cu la t ed us i ng th e S r Cr i s o f t en o ver e st im a te d i n e l de r l y i n di vi d ua ls
wi t h r e d uc ed m us cl e m as s . Th e r e i s a s t ro n g r e la t i on sh ip b et we e n th e ph a r ma co ki n et ic s o f
m e t fo rm i n a nd bo t h ki d ne y f u nc t io n a nd a ge . I n he a l th y e ld e rl y p a ti en t s, re n al cl ea r a nc e o f
m e t fo rm i n wa s 3 5% to 40 % lo we r t h an r es pe ct i ve va l ue s f o r h ea l th y yo un g in di vi d ua ls . 13 7
F i n al l y, t h e f a vo ra b le ef fe c t m et f o rm in ha s o n we i g h t is i rr e le va n t i n J . M. Th u s , al t ho ug h th e
e f f ic ac y o f m et f o rm in is c om p a ra bl e to th a t o f s ulf o n yl u re as , i t i s n o t t he a g e nt of f ir s t ch o ic e
f o r el d er l y pa t ie n ts s uc h a s J . M. 2 4 3
P a t i en ts wi t h F P G > 3 00 m g /d L a n d n o o ve r t s t re ss sh ou l d b e c on si de r e d in s ul in de f ic ie n t a n d
s t a rt e d o n i ns ul i n t he r apy.
Selecting a Sulfonylurea
B e c a us e h i s F P G c on c en t r a t i on s r em a in 20 0 to 2 5 0 m g /d L , t h e d ec i s ion i s m a de t o s t a r t
J . M . o n a su l f on yl u r e a . W h a t fa c t o rs sh o u ld be c o ns i d e re d in se l ec t i ng a su l f on yl u r e a f o r
J . M .?
Th e r e a re se ve r al ag e - as so ci a te d pr o bl em s wi t h t h e u se o f o r al h yp o gl yce m ic a g en ts . H ep a ti c
b l oo d fl o w a n d o xi d a t i ve m e ta b ol is m a r e d ec r ea se d wi t h a g in g , r es u lt i ng in p r ol on g ed ha l f -l i ves
o f he p at ic a ll y me t ab o li zed d r ug s. S e ru m a lb um in i s re d uc ed in th e e l de r l y, a n d t hi s a f fe c ts t h e
h i gh l y p ro t ei n - bo un d fi rst - g e ne r at i on s u lf o n ylu r eas , re s ul ti n g i n i nc r ea se d s e r um l e ve ls o f f re e
d r u g .2 46 R es p on se to h yp o gl yc em ic co un t e r -r e gul a t or y h o rm on e s is di mi ni s he d i n t h e e ld e rl y,
p r e di sp os i ng th e m t o p r ol o ng e d h yp og l yce mi a . De c r ea se d re na l fu nc t io n a n d m as s t ha t o cc u rs
wi t h a g in g d ec r e as es t h e c le a r an ce an d i nc r ea ses t he ha l f - l i ves o f o ra l ag e n ts e xc r e t e d
r e n al l y, s p ec if ic a ll y ac e to h e xa m i de , c hl o rp r o pa mi d e , a nd gl yb u ri d e. C hl o rp r o pa mi d e sh o ul d n o t
b e us ed in th e e l de r l y pop u la t io n o wi n g t o i ts l o ng h al f -l i fe ( ≥ 35 ho u rs ) and h ig h i nc id e nc e o f
h yp o g l yc em i a a nd h ypo na t r em i a. 2 46 O f t h e s ec on d - ge n e ra t io n a ge n ts , g li p i zid e i s p r ef e r r ed
o ve r g l ybu r id e i n f r a il , e ld e r l y pa t ie n ts l ik e J . M. Th i s is be ca u se i t s d u ra t io n of ac t io n i s sh o r te r
t h a n t ha t of gl yb u ri d e a nd i t is me t ab ol i ze d t o i n ac t i ve p r od uc t s. C on se q ue n t l y, i t i s 5 0% le ss
l i ke l y to ca us e s e ve re and p r ol on g ed h ypo g l yc em ia i n t he el d e rl y p op ul a ti on . 1 45 , 24 7 Th is i s a
c o nc e rn be ca us e s e ve ra l f a ct o rs p re di sp o s e th e el d e rl y t o d r ug - i nd uc ed h yp o gl yc em i a. Th es e
i n cl ud e a n o re xi a , i r re g ula r o r i na d eq u at e f o od in ta k e, an d o t he r f ac to r s a ff e c ti ng nu t r it i on (s e e
Q u e s ti o n 7 3 ) . To l bu t am id e ( wh i ch is c on ve r t ed to i na ct i ve m e ta bo l it es ) , g l im ep i r id e ( wh i c h h as
b e e n st u di e d i n r en a l i nsu f f ic ie nc y) , an d re p ag li n id e 1 43 an d n a te gl i ni de (wh i c h a re ve r y sh o rt a c ti n g ) a re al so a p p r op r ia t e o p ti o ns .
Maturity-Onset Diabetes of the Young
B . L . is a 3 4 - ye a r - o l d , s le n d e r ( 5 ′ 6″ , 12 0 l b , BM I 1 9 .4 k g/ m 2 ) w o m an w ho d e ve l op e d
d i a be t e s a t th e a g e o f 23 . U n t il r ec e n t l y, h e r d ia b e t es w as ve r y w e ll co n t r o l le d ( A 1 C , 6 % t o
7 %) o n g l i p iz i de 5 m g da i l y. Ap p r o x i m a t e l y 3 m o n t h s a g o, he r p h ys i c i a n d i sc o n ti n ue d
g l i p iz i de an d be g an t r ea t i n g h e r w i th ve r y l o w d o s es o f i n su l i n ( 7 u n i ts o f 7 0 /3 0 in s ul i n
tw i ce da i l y) w h en s he an n o u nc e d h e r i n t en t i o n t o b ec om e p re g na n t . How e ve r , s h e i s
e x p e ri e nc i n g f r e q ue n t h yp o g l yc e m i c r ea c t io ns a nd w o u ld l ik e to sw it c h ba c k t o gl i p iz id e .
B . L . ha s no o th e r me d ic a l p ro b le m s, a nd he r p h ys i c a l e xa m in a t io n is w i t h i n n o rm a l l i mi t s .
B . L . ' s m o th e r ( on s et a t a g e 3 2 ) a n d yo u n g e r s is t e r ( on s e t a t a g e 2 5) al s o ha ve d ia b e te s
a n d a r e w e l l c on t r o ll e d o n o ra l ag e n ts . As s es s B . L . 's d ia b e te s . H ow sh o u l d s he b e
m a n ag e d?
I t is qu i te li ke l y th a t B . L . h as a r e la t i vel y r a r e f o rm o f d ia be t es of t en r ef e rr e d to as ma tu r i ty o n se t d i ab e te s o f t h e you n g ( MO D Y) . 2 4 8 Typ i c a ll y, t h e p at i en t i s n o rm al we i g h t , h a s a s t ro n g
f a mi l y hi s to r y o f d ia be t es , an d i s d ia g n os e d d u rin g hi s o r h e r you n g - a du lt ye a r s. 2 49 U nl ik e
o b es e p a ti e nt s wi t h t yp e 2 d ia be t es , ti ss ue s e ns it ivi t y t o in su l in ac ti o n is no r m al , b u t i ns ul in
s ec r e ti o n i n r es p on se to g l uc os e i s d ef e ct i ve . C on s eq u en t l y, p at i en t s su ch as B . L. r es po n d t o
o r a l s ul f on yl u re as an d l ow d o s e s o f i ns ul i n. Th e ph ys ic i an ' s d ec is i on to t rea t B .L . wi t h i ns u li n
i s ra t io n al b e ca us e s he in t e nd s t o c on ce i ve a n d o r a l s ul f on yl u re as cr os s t h e p l ac en t al ba r r ie r ;
h o we ve r , i t a pp e a rs a s th o u gh he r d o se an d r e gim e n wi l l ha ve to be ad j us t ed .
Complications
N o t e to th e re a de r : A t hor o u gh an d e xt e n s i ve d is cu ss i on ad d re ss i ng th e c lin i ca l p r es en t a ti on o f
d i ab e ti c c om pl ic a ti o ns i s b e yo nd th e s co p e o f t his ch ap t e r . Th u s, t he fo l lo wi n g ca se s a nd
r e s po ns es a re p re se n te d o n l y to gi ve th e b e gi nn in g c l in ic ia n a f la vo r of the p r es en t at i on of
s om e o f th e m os t c om mon co mp l ic at i on s a nd a g en e r al ap p r oa ch to t he i r t re a tm e nt . Al s o se e
C h a p te r s 1 4 , E ss en t ia l Hyp e r t e ns io n , a nd 32 , C hro n ic K id ne y D i se as e .
L . S . is a 4 6 - ye a r - o l d , ob e s e m an w i t h a n 8 - ye a r h i s t o r y o f t yp e 2 d i abe t e s . H i s c u r r en t
p r o b l em s i n c lu d e a B P o f 1 55 / 10 3 m m Hg ( d ocu m e n te d o n tw o o c ca s io n s ) , b l u r r y vi s i o n ,
a n d s e xu a l i m po t e nc e , w h ic h he now a dm i t s ha s t r ou b l ed h im f o r t h e l a s t few ye a r s .
P h ys i c a l e xa m in a t io n re v e a l s d e c re a se d pe d al p u l se s b i l at e r a ll y, l o s s o f se n sa t i o n t o
m o n o fi l am e n t t e s ti n g , a n d e vi d e n ce o f a n a mp u t a t ed t oe on t h e r i g ht f o o t . H i s l a bo r a t o r y
va l u e s a r e as f ol l ow s : F P G , 1 70 mg / d L ( n o rm al , 7 0 t o 1 0 0) ; A 1 C , 7 . 8 % ( n o r m al , 4 t o 6 %) ;
f a s t i ng ch o l es t e r ol , 2 40 m g/ d L ; a n d t r i g l yc e r i d e s , 1 60 m g/ d L. L . S. h as n o r ma l e l ec t r o l yt e
va l u e s a n d m i c ro a l bu mi n u r i a ( 1 80 µ g /g c re a t i ni n e ) . Hi s o n l y m e d i c a t io n i s g l ip i zi d e 1 0
m g / da y. D e s c r i b e t h e pa t h o ge n es i s o f h yp e r t e n s i o n i n p a t ie n ts s uc h a s L .S . Wh y i s i t
i m p o r ta n t t o t r ea t L . S. 's h yp e r t e n s i o n ?
[ S I un i ts : F P G , 9 .4 m mo l/ L ; fa st i ng c h ol es t e ro l , 13 . 3 m mo l /L ; t r i gl yc er i de s, 8 . 9 mm ol / L]
Hypertension
H yp e r t e ns io n i s t he ma in d e te r mi n an t o f l i fe e xp ec t an c y an d c om pl ic a ti o ns in di a be t ic p a ti e nt s
a n d d e te r mi ne s t h e e vo lu t i on of di a be t ic n e ph r opa t h y an d re t in o pa t h y, i n p a r ti c ul a r. P at i en t s
wi t h t yp e 1 d ia be t es us ua l l y ar e no rm o te n si ve i n t h e a bs e nc e o f n e p h r op at h y, b ut bl o od
p r e ss u re s r is e 1 to 2 year s af t e r t h e o ns et of in cip i en t ne p hr o pa t h y a s i n di c at e d b y
m ic r o al bu mi n u ri a ( se e Qu e st i on 79 ) . Th us , h yp e rt e ns i on in a p at i en t wi t h t yp e 1 d ia b et es
u s ua ll y i s o f r e na l p a re nc h ym al o r i gi n . Th e r el a tio n be t we e n h yp e r te ns i on a n d t yp e 2 di ab e te s
i s m o re c o mp le x a n d no t a s c lo se l y c o r re l at e d t o n e p hr o pa t h y. I n t ype 2 di a be t es , h yp e r te ns i on
i s o f t en pa r t o f t h e m et ab o li c s yn d ro me of in su l in r e si st a nc e . H yp e r te ns i on ma y b e p r es en t fo r
ye a r s o r de ca d es i n th ese p at i en ts be f o re o ve rt di a be t es
P . 5 0 -7 5
m e ll i tu s is de mo ns t r ab l e. H yp e r i ns ul in e mi a ma y co n t ri b u te to th e p a th o gen e si s o f h yp e r te ns io n
b y d ec r e as in g re na l e xc r e t i on of so di um , s t im ul a ti n g a ct i vi t y of an d t is s ue r e sp o ns e t o t h e
s ym p at h et ic ne r vo us s yst e m , a nd in cr e as in g p e rip h e ra l vas cu la r r es is ta nc e th r ou g h va sc ul a r
h yp e r t ro p h y.
A g g r es si ve m a na g em en t o f h ype r te n si on ( <1 3 0/ 80 mm H g ) r ed u ce s t he p ro g r es si on o f b ot h
m ac r o vas cu l a r a nd m ic r ova s c ul a r co mp l ic at i on s an d is e ss e nt ia l i n L . S . 176 , 1 77 , 25 0 , 2 5 1 I n t h e
U K P D S , a 5 - mm H g r e duc t io n i n m ea n d i as to l ic b lo o d p r es su r e p r od uc e d a 3 7 % r e du ct i on in
m ic r o vas cu l a r co mp l ic at io n s. 1 76 , 17 7 Ma n y p a ti ent s re q ui r e t wo o r th r e e me d ic a ti on s t o
a c hi e ve d t he ta r g et bl o od p r ess u r e g oa l o f < 1 30 /8 0 m m Hg . W eig h t r e du ct i o n a nd e xe r c is e
d e c re as e i ns ul i n r es is t anc e (a n d t he r e fo r e h yp e rin s ul in e mi a ) a nd wi l l b e ad d i ti ve to
m e di ca t io ns in lo we r i n g th e B P . D i et a r y so di um re s t ri ct i on ad d re ss es t he i n c re as ed t ot a l b od y
s o di um fo u nd in th es e pa t i en ts se co n da r y t o i nc re a se d s od i um re t en t i o n .
W h a t m u s t b e c o ns i de re d i n s el e c ti n g a n a n t ihyp e r t e n s i ve a g en t f o r L. S . ?
S i n ce nu me r ou s s tu d ie s h a ve do cu me n te d th e e f fe c ti ve n es s o f A C E in h ib it o r s a nd an g io t en si n r e c ep t or bl o ck er s (A R B s) i n re t ar d in g t h e d e vel op m en t a n d p r og r es si on of n ep h r op a th y, t h e se
a g e nt s a r e a pp r op r i at e as in i ti a l t he r ap y f o r t h e m a na g em en t o f h ype r te ns i on in pa t ie n ts wi t h
d i ab e te s . Th e ch oi ce o f a se co n d a ge n t f o r t h e ma n a ge me n t o f h yp e rt e ns io n in pe r so ns wi t h
d i ab e te s i s mo r e c on t r o ve r s ia l. D a ta su pp o r t t he b e n ef i ts o f β - bl oc k e r s. No d if f e re nc e wa s
d i sc e rn ed be t we e n pa t ien t s r a nd om i ze d t o a t en olo l or ca p to p ri l a s i ni t ia l th e r ap y i n t h e
U K P D S . 1 7 7 O wi n g t o t h e h i gh p re va le nc e o f C H D i n p e op le wi t h di a be t es , a β - bl oc ke r is
p r e f er r e d as se co n d - l in e t h e ra p y in m o st pa t ie n ts. Th i a zi de di u re t ic s a r e al s o as so ci a t ed wi t h
c l ea r t re a tm en t b e ne f it s a n d i mp r o ved ou t co me s f o r pa t ie n ts wi t h d ia b e tes . Fo r A f ri ca n A m e ri c an pa ti e n ts , d iu r et i c t h er a p y m a y be a b et te r ch o ic e as a s ec on d -l in e ag e nt . C er t ai n l y, i f
e i t he r th e f i rs t - o r s ec o nd - l in e t h e ra pi e s f ai l t o ac h ie ve a B P < 1 30 / 80 mm H g , t he n a l l t h re e
a g e nt s s ho ul d b e u se d in co mb i na t io n . O t h e r a ge n ts , s uc h a s c al ci um c ha n n el b l oc ke rs ,
p e r ip h e ra l va s od il a to r s, a n d c en t r al l y ac ti n g a gen t s h a ve s om e wh a t l es s d e si r ab l e e f fe ct s wi t h
r e s pe ct t o di a be t es an d a r e no t p r e fe r r ed o ve r AC E i n hi bi t o rs , A R Bs , β- bl o ck e rs , a nd di u r et ic s.
Th e m an a ge me n t o f h ype r t e ns io n i n p eo p le wi t h d i ab e te s i s d isc u ss ed in C h a p te r 14 , Es se n ti al
H yp e r t e ns io n . A d ve rs e ef f e ct s o f a n ti h yp er t en si ve a ge n ts o f pa r ti c ul a r imp o r t an ce to pa t ie n ts
wi t h d i ab e te s a r e su mm ar i ze d i n Ta bl e 5 0 - 35 .
Table 50-35 Antihypertensive Agents: Important Adverse Effects in Patients with Diabetes
Drug
Blood
Lipid
Glucose Profile
Impotenc Insulin
e
Sensitivity Proteinuria
Comments
First-Line Antihypertensive Agentsa
ACE
inhibitors
↑
Neutra
l
Rare
↑
↓
May cause
hyperkalemia
in patients with
impaired renal
function
ARBS
(angiotensin
receptor
blockers)
↑
Neutra
l
Rare
↑
↑
May cause less
cough than
ACE inhibitors
↓
↓
Can prolong
and mask
hypoglycemic
symptoms
Second-Line Antihypertensive Agentsb
βAdrenergic
blockers
↑↓
↑ TG
↓ HDL
+
(most
important in
patients on
insulin and
with long-term
type 1 DM).
Response to
counterregulatory
hormones may
be exaggerated
due to
unopposed αeffects (e.g.,
arrhythmias,
hypertension).
Cardioselectiv
e agents may
be preferable.
Hyperosmolar
nonketotic
coma may
occur in
patients with
endogenous
insulin.
Unopposed αeffects may ↓
peripheral
circulation
Thiazide
diuretics
↑
↑ Chol
↑ TG
+
↓
↓
Commonly
used in low
doses.
Hypokalemia
can ↓ insulin
secretion,
cause tissue
resistance, and
promote
arrhythmias.
Diabetogenic
effects most
prevalent in
type 2 DM. To
minimize
metabolic
effects, do not
exceed 25
mg/day HCTZ
or use
indapamide 2.5
mg/dL
Third-Line Antihypertensive Agents
Calcium
channel
blockers
Non
e
Neutra
l
Rare
No
effec
t
Variable
Nifedipine
potentially
may worsen
proteinuria
αAdrenergic
blockers
Non
e or
↑
↓
LDL-C
↑
HDLC↓
TG
Rare
↑
Unknow
n
First-dose
hypotension
Central
adrenergic
inhibitors
Non
e
None
++
No
effec
t
No effect
Sedation,
depression, dry
mouth, sodium
retention,
orthostasis
Peripheral
adrenergic
inhibitors
Non
e
None
+++
No
effec
t
No effect
Orthostasis;
sodium
retention
usually
requires
addition of
thiazides
Vasodilator
s
Non
e
None
Rare
No
effec
No effect
Tachycardia
and sodium
t
retention
require
addition of
thiazide and βblocker
a
These agents are preferred because they have minimal adverse metabolite effects. Agents
are listed in general order of use; individualize selection to patient needs.
b
These agents are not contraindicated, but are not preferred because of adverse effects on
glucose and lipid metabolism or sexual function.
ACE inhibitors, angiotensin-converting enzyme inhibitors; Chol, cholesterol; DM, diabetes
mellitus; HCTZ, hydrochlorothiazide; HDL-C, high-density lipoprotein cholesterol; LDLC, low-density lipoprotein cholesterol; TG, triglycerides.
P . 5 0 -7 6
Nephropathy
Th i c ke n in g o f th e g lo me ru l a r c ap il l ar y b as em e nt m em b r an es is th e h al lm ar k of di a be t ic
n e p hr o pa t h y. Di f fu se d ep o si t io n o f b as em e nt mem b r an e – l ik e ma t e ri a l e xp a n ds t h e m es an gi um .
Th i s p ro ce ss na r r o ws the ca p il la r y l um in a , im p ede s b l oo d f l o w, an d th e reb y r e d uc es th e
f i l te r in g s u r fa ce ar e a i n th e gl om e ru l us . H ype r gl yc em i a ca u se s i nt r ag l om er u l a r h yp e rt e ns io n
a n d re na l h yp e r fi l t ra t io n . H yp e r f il t r at i on th e n is f ol l o we d b y m ic r oa lb um i nur i a wi t h m in im al
g l om e ru l osc l e ro si s, wh i ch s ti ll is p o te n ti a ll y r e ve rs i bl e . I f a p pr o p ri a te th e ra p y is no t in i ti at e d ,
o ve r t p ro t ei nu r i a oc cu r s a n d t h e p at i en t u su a ll y pr o g r es se s t o n ep h r ot ic syn d r o me . P ro g re ss io n
o f di a be t ic re n al di se as e c an be ac ce l er a te d i n the p r es en ce of h ype r t en sio n , p r o te i nu r ia , 25 2
a n d d ia b e ti c r e ti no p at h y ( a n o th e r mi c ro va sc ul a r co m pl ic a ti on ) . Li pi d a b no rm a li t ie s a l s o ma y
c o nt r i bu t e t o t he p ro g r ess i on of gl om e r ul os cl e ro sis .
Screening and Confirmation of Microalbuminuria
Mi c r o a l bu mi n u ri a i s d ef in e d a s a u r i na r y al b um in e xc r e t i on ( U A E ) o f 2 0 µg / mi n ut e o r >3 0 m g /2 4
h o u rs or 3 0 mg al b um in /g c re a ti n e d ur i ng a r a ndo m u r i ne c o ll ec t io n . B eca u se of da y - t o - da y
va r i a bi l it y i n a lb um i n e xc r e t io n , a t l e as t t wo o f th re e u ri ne sa mp le s c ol le c te d in a 3 - t o 6 - mo n th
p e r io d n e ed to ha ve el e va t e d l e vel s b ef o r e t he des i gn a ti on o f mi c ro a lb um in u r ia . 5 , 7 3 , 2 5 3
Mi c r o a l bu mi n u ri a r a r el y o cc u rs in t yp e 1 p a ti e nt s wh o a r e you n ge r th a n 14 ye a rs o f a ge or in
t h os e d i ag n o s ed fo r <5 ye a r s. Th e r ef o r e, pa t ie n ts wi t h t yp e 1 di a be t es s hou l d b e sc r e en e d f o r
m ic r o al bu mi n u ri a a nn u all y a f t er 5 yea r s o f d ia b ete s o r at t he on se t o f pu be r t y. P a ti en t s wi t h
t yp e 2 d ia b et es sh o ul d be sc r ee n ed an n ua ll y f r om t he ti me of di a gn os is . Th e d e ve lo pm e nt of
h yp e r t en si on , o r a n y i nc re a se in th e c on c en t ra t ion o f S r C r , a n d r e ti n op a thy a r e in d ic at i on s f o r
m o r e f r eq ue n t sc r e en in g f o r m ic r oa l bu mi nu r i a. Me a su r em e nt of t he al bu mi n :c r e at i ni ne r at i o
f r o m a ra n do m sp o t u r ine co l le ct i on ( pr e fe r a bl y th e fi r st - vo i d o r m o rn in g s am p le ) is t h e
p r e f er r e d l ab o ra t o r y te st f o r a ss es si n g mi c ro al b um i nu r ia . U ri n e a lb um i n co n ce n t ra t io ns c a n b e
f a ls e l y e l e vat e d b y e xe r ci s e, e xc e ss i ve p r ot e in in ta k e, un c on t ro l le d d ia b ete s , u nc o nt r ol l ed
h yp e r t en si on , an d u r in a ry t r a c t i nf ec t io n . Th er e for e , s c re e ni n g sh o ul d b e d e la ye d i f a p at i en t
h a s o ne of t he se c o nd i tio n s.
A f t e r t h e d ia g no si s o f a lb u mi n ur i a, an d i n it i at i on o f an A C E i n hi b it o r o r AR B , t h e r ol e o f an nu a l
m ic r o al bu mi n u ra ass es sm e nt is no t we l l es t ab l ish e d . 2 5 3 H o we ve r , we r ec om me n d c on t in ue d
m o ni t o ri ng t o as se ss re sp o ns e t o th e ra p y an d p ro g r es si on o f d is ea se .
W h a t i s th e si g ni f i ca n ce o f th e p re s en c e o f a lb u m i n i n L . S . 's u ri n e ? H ow s h o ul d i t b e
m a n ag e d?
D i a b et ic ne p hr o pa t h y, c ha r a ct e ri ze d b y n e ph r ot ic s yn d r om e a nd a zo te mi a , a cc ou n ts fo r 35 % o f
a l l p a ti en t s wi t h E S R D . It i s a m aj o r c au se of de at h in pa t ie n ts wi t h t yp e 1 d i ab e te s a nd is a n
i n c re as in g s ou r ce o f mo rb i di t y i n t yp e 2 di ab e ti c in d i vid u al s. 2 53 , 25 4 L . S . h a s mi c ro a lb um in u r ia
( 1 8 0 m g a lb um in / g c r ea tin e ) . De p en di n g o n t h e me t h od of me as u re me n t , m ac r o al bu mi n u ri a , o r
o ve r t ne p h ro pa t h y, i s d efi n ed as >3 0 0 mg / g c r ea tin i ne , >2 0 0 µ g /m in , o r >3 0 0 m g/ 2 4 -h ou r
c o ll ec t io n . Ma n a g em e nt in c lu d es e a r l y d e te ct i on th r o ug h s c re en i ng fo r m icr o a lb um i nu r ia ; ti gh t
g l uc os e c on t r ol ; A C E i nhi b i to rs a nd A R Bs fo r pa t ie n ts wi t h m ic r o al bu mi n u ri a ( to s l o w
p r o g re ss io n ) ; a gg r es si ve m an a ge me n t o f h yp e r ten s io n , wh i c h c an acc e le ra t e d e te r i or a ti o n o f
r e n al f un ct i on ; a g gr e ss i ve ma n ag em e nt o f d ysl i pid e mi a ; a nd s mo ki n g c ess a ti o n. 2 52 A th o ro u gh
d i sc us si on on t he m a na ge m en t o f di ab e ti c n ep h r op a t h y a n d E S R D is di sc us se d i n C ha p te r 3 2 ,
C h r o ni c Ki dn e y D is e as e.
Cardiovascular Disease
L . S . is t r ea t e d w i t h li s in o p r i l 2 0 m g d a i l y, w hic h co n t r o ls h is B P a n d i m p r o ve s h i s
m i c r oa l b um i n u ri a . Hi s d o s e o f gl i p iz i de is t i t ra t e d to 10 mg d ai l y. R e c e n t l a b o ra t o r y
va l u e s in c lu d e a n F P G o f 1 30 mg / d L, A 1 C o f 6.0 % ( n o r m a l , 4 % t o 6 %) , a t r i gl yc e r i d e l e ve l
o f 4 50 mg / d L ( n o rm a l , < 1 5 0 m g/ d L ) , t o ta l ch o le s t e r ol o f 1 60 m g/ d L ( no r m a l , < 2 0 0 m g /d L ) ,
a n d H D L c h ol e s te r o l o f 2 0 m g / dL ( no r m a l, >4 0 m g / d L) . H ow do e s t h e ri s k of h ea r t di s ea s e
f o r p a t ie n ts s uc h a s L .S . c om p a r e w i t h p e r s ons w i t h ou t d ia b e te s ? W ha t i s t h e
p a t h og e ne s is o f C H D i n p e r s on s w i th d ia b et e s?
[ S I un i ts : F P G , 7 .2 m mo l/ L ; A 1 C , 0. 0 7 ; t r ig l yce r ide s , 7 . 34 m mo l /L ; to t al c ho l es t e ro l , 8 .9 m mo l /L ;
H D L , 0 .5 2 m mo l/ L ]
C H D i s th e l ea d in g c au se o f p r em at u r e d ea t h i n th e t ype 2 p op u la t io n a n d a cc ou n ts fo r 50 % o f
t h e d e at hs in pe o pl e wi th d ia be t es . R en al co mp lic a ti o ns o f t ype 1 d ia b et es we r e p re vi o us l y th e
p r i nc ip a l ca us e o f de a th ; h o we ve r , wi t h th e a d ve nt o f d ia l ys is a n d r en a l t ra n sp l an t at i on ,
c a r di o vas cu l ar co mp li ca ti o ns ha ve be co me t he pri n ci pa l c au s e o f mo r b id i ty a n d m o r ta li t y.
R e l a ti ve to no n d i a be t ic in d i vid u al s, t ho se wi t h dia b e te s a r e t wo t o t h r ee ti m es m o re li ke l y to
d e ve l op C H D , a n d t he i r ri sk o f d ea t h f ol l o wi ng an MI a l s o i s t wo t o th r ee tim es hi g he r th a n
t h e ir n on di a be t ic c ou n te rp a r ts . W ome n wi t h d ia b et e s , r eg a r dl es s o f t h ei r ag e o r me n op au s al
s t a tu s, ha ve eq u al r isk fo r C H D t o t ha t of no n di ab e t ic m en . Th es e s ob e r in g fi g u re s p oi n t t o t he
i m po r t an ce of mi ni mi zi n g o r el im in a ti n g a ll ot h e r p r e ve n ta bl e ri sk fa ct o rs fo r ca r di o va sc ul a r
d i se as e i n p a ti e nt s wi t h d i ab e te s (i . e. , to ba cc o us e , h yp e r t e ns io n , h yp e rch o le s te r ol em i a,
o b es i t y) t h r ou g h t he p res c ri p ti o n o f e xe r c is e , d iet , a nd ap p ro p ri a te me di ca t i on s. 2 55
Pathogenesis
Th e p a th o ge n es is o f c a rd i o vas cu l ar di se a se in pe o pl e wi t h d i ab e te s is com p le x. Th e m e ta b ol ic
s yn d r om e wi t h i ts a t t en da n t c a rd i o vasc u la r ri sk fa c to r s , d ysl i pi de mi a , i nf la mm a ti o n, an d
h e mo st a ti c a b no rm a li t ie s a r e o n l y s om e o f t h e mec h an is ms un de r s t u d y. 1 3 , 2 5 6
Th e m os t c om mo n l ip i d ab n o rm al i t y i n t ype 2 d ia be t es is h ype r t ri g l yc e r id em i a ( > 15 0 m g/ d L )
wi t h l o w l e ve ls of H D L ch o le s te r ol ( <4 0 m g /d L i n m al es o r < 50 m g /d L i n f e ma l es ) , si mi l a r t o
t h e l i pi d p r of i le s e en in L. S . 2 57 , 25 8 Po o r c on t r ol o f t yp e 1 d i ab e te s a ls o is as so ci a te d wi t h
e l e va te d L D L c ho l es te r o l l e ve ls a s we ll as h ype r t ri g l yce r id em i a. 2 58 A ll of th e se li pi d
a b n or ma l it i es c on t r ib u te t o t he ri sk fo r c a r di o vas cu l a r d is ea se .
A l t h ou gh p ri ma r y p r e ven t i o n t r ia ls s p ec if ic a ll y e va l ua t in g l i pi d l o we r i ng in p e rs o ns wi t h
d i ab e te s h a ve n o t b ee n p e r f or me d , t wo s u bg r ou p a n al ys es of la r ge - sc al e s ec o nd a r y p re ve n ti o n
t r i al s h a ve b e en pe r f or me d . In th e Sc an d in a via n S i m vas t a ti n S u r vi va l S t ud y ( 4 S S tu d y) , wh i ch
wa s a mu l ti ce n te r , ra nd om i ze d, pl ac e bo - co n t ro ll ed t r ia l , 2 02 of t he 4, 4 44 s u bj ec ts h ad
d i ab e te s . 2 5 9 S u bj ec ts we r e ra n do mi ze d to s im vas t a ti n ver s us p l ac eb o . Th e ri sk r ed uc t io n o f
C H D i n di ab e ti c s ub je c ts r e ce i vi ng t re a tm en t wa s 5 5 % ve r su s 3 2% in no nd i ab e ti c s ub j ec ts .
A n o t he r s ec o nd a r y pr e ven t i on t ri al , th e Ch o le st e ro l an d Cu r r en t E ve nt s ( CA R E ) S t u d y,
e xa m i n e d t he ef f ec ts o f tr e a tm e nt wi t h 40 m g d a ily o f p ra va s ta t in ve rs us pl a ce b o in
P . 5 0 -7 7
5 8 6 p a ti e nt s wi t h di a be te s . 2 6 0 , 2 61 Tr e a tm en t wa s a ss oc i at e d wi t h a 2 5% d ec r ea se in m a jo r
C H D e ve n ts , s im i la r to a 2 3 % d ec r ea se in no n di ab e t ic s ub j ec ts . Th es e s tud i es de mo ns t r at e th e
k e y r ol e o f L D L c h ol es t er o l i n th e g e ne si s a nd pro g r es si on o f a th e r osc l ero s is . An o th e r
i m po r t an t f i nd in g i s t h e 2. 5 - f ol d h ig h e r C H D r is k ob s e r ved in di ab e ti c s ub jec t s ve r su s
n o n di ab e ti c s ub je c ts , i ndi c at i ng th a t d ia b et ic su bje c ts wi t h a hi s to r y o f p r io r MI a r e at a ve r y
h i gh r is k f o r f ut u r e d is eas e .
A d u l ts wi t h d ia b et es sh ou l d b e sc r e en e d a nn ua l ly f o r se r um li po p r ot ei n le ve l s, in cl u di n g
t r i gl yc e ri d es , t o ta l c ho l es t e ro l , L D L c ho le s te r ol , a n d H DL ch ol e st e ro l . A t o t a l ch o le st e r ol le ve l
o f <2 0 0 m g/ d L, t ri g l yc e rid e le ve l < 1 50 m g /d L , a nd L D L c ho le s te r ol le ve ls m a in t ai ne d a t ≤ 10 0
m g /d L a r e a cc ep t ab l e. I n a lm os t al l i ns ta n ce s, a st a t in sh ou l d b e us e d i n pa t i en ts wi t h
d i ab e te s . Th e A D A no w r e c omm e nd s s ta t in th e r ap y i n p a ti e nt s o ve r th e ag e of 40 wi t h a TC
≥ 1 3 5 m g /d L r e ga r dl es s of b as el i ne L DL le ve ls . 257 F o r t ho se pa t ie n ts wi t h d i ab e te s a nd k n o wn
a t h e ro sc le r o ti c co r on a r y a r t e r y di se as e , a s t at i n is o ve r wh e lm in g l y i n di ca te d . 25 7
Dyslipidemia
S h o u l d L . S . b e t r e a te d w i t h d r u g t h e ra p y f o r h i s d ys l i p i d e m i a?
D i e t a n d e xe r c is e a r e c or n e rs t on e s i n t he m a na ge m en t o f d ys l ip id em i a i n p a t ie n ts s uc h a s L . S .
W eigh t l os s i s as so ci a ted wi t h im p ro ve me n ts in in s ul in se ns i ti vi t y an d g l uc os e c o nt r ol , as we l l
a s a r ed uc t io n i n t r i gl yc er i d es , t o ta l c ho l es te r o l, a n d L D L c ho l es te r o l. P hys i ca l a c ti vi t y
e n h an ce s we i g h t l os s a nd i nc r ea se s H D L c h ol es te r o l l e vel s . Th u s, L . S. ' s d i e t a nd e xe r c is e
h a bi t s sh o ul d b e re as se ss e d a nd in st r uc t io n i n b ot h r ei n fo r ce d a s a pp r op r ia t e . B l oo d g l uc os e
c o nc en t r at i on s sh o ul d be o pt im a ll y co n t ro ll e d wi t h d ie t , e xe r c is e , a n d o ra l a g en ts o r i ns ul i n
wh e n i n di ca t ed . Ho we ve r , t h e a tt a in me n t o f d ia b et e s c on t r ol i n p a ti e nt s wit h t yp e 2 d i ab e te s
d o es no t n e ce ss a ri l y c o rr e c t l ip id ab n o rm al i ti es , a s s ee n i n L . S . Be ca us e i n su li n re si s ta nc e
m a y be t he un d er l yi ng ca u se of el e va te d l i pi ds in t he se pa t ie n ts , e f f or t s s h ou l d b e d e vot e d t o
r e ve r si n g i ns ul i n r es is t an c e as we l l . Be ca us e L .S . ' s F P G a n d A 1 C va lu es i n di ca t e t ha t he ha s
a c hi e ve d d ia be t es c o nt ro l , a li pi d - lo we r i n g a ge n t i s wa r r an t ed if he do es n o t re sp o nd to
l i f es t yle mo di f ic at i on s .
Bile Acid Sequestrants
B i l e a ci d s eq ue s t ra n ts p ri m a ri l y l o we r t o ta l a nd LD L c ho le s te r ol le ve ls wi th l it t le ef f ec t o n H D L
c h ol es t e ro l . Th e se ag e nts ca n e le va t e t r i gl yc er i de l e vel s a nd m a y b e p rob l em a ti c as
m o no t he r ap y f o r p a ti e nt s s uc h a s L . S . wi t h m i ld to mo d e ra t e h yp e rt r ig l ycer i d em ia . L o w d o se s
o f bi l e ac i d se q ue st r a nt s m a y be us ef u l as ad j un ct i ve t he r ap y wh e n co mb in e d wi t h a fi b ri c a ci d
d e r i va ti ve or an H MG C o - A r e du c ta se in hi b it o r .
Fibric Acid Derivatives
G e m f ib r o zil an d fe no f ib ra t e a r e t h e f ib r ic ac id der i va t i ves cu r r en t l y a va i lab l e i n t h e U n it e d
S t a t es . Th es e d r ug s ac t iva t e li p op r o te in li p as e, wh i c h r ed uc es t ri g l yc e r ide s a n d i nc r ea se s H D L
c h ol es t e ro l . Th e y e xe r t a va r i a bl e b u t g en e ra l l y mo d es t L D L c h ol es t e ro l – l owe r i n g e ff ec t .
G e m f i b r o zil o r f en o fi b r ate ma y b e u se f ul in pa t ien t s l ik e L . S . wh o s e d ys lip i de mi a i s
p r e do mi n an t l y c ha r ac t e rize d b y h yp er t r ig l yce r id em i a. G em f ib r o zil sh o ul d n o t b e u se d i n
c om b in a ti o n wi t h r ep a gl in i de ( se e Ta bl e 5 0 -3 1 ) .
HMG-CoA Reductase Inhibitors
S i m vas t a ti n , p ra va s ta t in , l o vas t a ti n , f lu va s ta ti n , at o r va s t a ti n , a n d r os u vas ta t i n i nh ib i t H MG C o A r e du ct as e , a k e y r eg u la t o r y en zym e fo r c h ole s te r o l b io s ynt h es is . As a r es u lt , h e pa t ic
c h ol es t e ro l s yn th es is dec l in es , s u rf a ce L DL pa r t ic l e r ec e pt o rs in c re as e , an d L DL ch ol es t e ro l
c l ea r an ce in c re as es . The s ta t in s’ li pi d e f fe c ts a re d os e -d ep e nd e nt . R os uva s t a ti n a nd hi g he r
d o se s o f a t o r vas ta t in and si m vas t at i n ca n h a ve a s ub s ta n ti al e ff ec t on t rig l yc e ri de s , wh i c h is
h e lp f ul in pa t ie n ts wi t h el e va t io ns in bo t h L D L c ho l es t e ro l a nd t ri g l yc e r id es . Th e y r ai se H D L
c h ol es t e ro l s li gh t l y.
Niacin
N i a ci n e f fe c ti ve l y lo we r s L D L c h ol es t er o l. H o we ve r , it ha s a do se - de p en de n t e f f ec t i n
i n c re as in g p l asm a g l uc os e . Al th o ug h p r ec is e m ec h an is ms b y wh ic h th is oc cu r s a r e u nk no wn , i t
m a y be du e to acc e n tu a ti o n o f i ns u li n r e si st a nc e. Th e r e f o re , n i ac in ' s u se a s fi rs t - li n e t he r ap y
f o r d ysl ip i de mi a i n p eo p le wi t h di a be t es i s n o t r ec om me n de d . 2 5 7 W hil e two s t u di e s h a ve
d e mo ns t r at e d a m in im a l g l yc em ic e f f ec t ( i nc r ea ses in bl o od gl uc os e b y 9 m g /d L a n d A 1 C 0. 3 %) ,
p r a ct i ti o ne rs st i ll re se r ve i t s us e a s t hi r d -l i ne th e ra p y wh e n co mb in a ti o n t he r a p y is
i n di ca t ed . 2 62 , 26 3
B e c au se h ype r t r ig l yce r ide m ia is th e m ai n a bn o rma l i t y i n L . S . 's li p id pr o fi le , ge m fi b ro zi l i n a
d o se of 60 0 m g t wi c e da il y o r fe n of i b ra t e 6 7 mg da i l y c a n b e us e d t o a t ta in a tr i gl yc e ri de le ve l
o f <2 0 0 m g/ d L. A ls o se e C h a p te r 13 , D ysl i pi de mia s , a nd r e vie ws o n t h is su b je c t. 2 57
Retinopathy
L . S . is r e fe r r e d to t he op h t h al m o lo g is t f o r h i s p e r s is t e n t c om p la i n t s o f vi s i o n p r o bl e ms
d e s pi t e im p r o ve me n t i n h i s g l yc e m i c c o n t r ol . H e i s d i ag n o se d w i th mi l d ba c kg r o u nd
r e t i n o pa t h y. S h o u l d L .S . b e c o nc e r ne d ?
O c u l ar di so r d er s re la t ed t o di a be t es a r e t h e l ea d in g c a us e o f n e w c as es of l eg a l b li nd n ess in
A m e ri c an s. P at i en ts wi t h d i ab e te s ma y e xp e r i e nce b lu r r ed vis i on as so ci a te d wi t h p o o r g l yc em ic
c o nt r o l, bu t re t in o pa t h y, s e ni le - t yp e c at a r ac ts , a nd g la u c om a a r e t h e co mp l ic a ti on s t h at
t h r e at e n si g ht . D ia be t ic re t i no pa t h y ap p ea r s as ea r l y as 3 ye a rs a ft e r d iag n os is an d i s e vi de n t
i n 90 % o f t yp e 1 d ia be t ic i n di vi du a ls a f t e r 1 5 ye a rs . C om pa r ab l e f ig u r es f or p a ti e nt s wi t h t yp e
2 d ia be t es t re a te d wi t h in s ul in an d t ype 2 p at i en ts t re a te d wi t h d i et an d or a l a g en t s a re 80 %
a n d 5 5 %, r es pe ct i ve l y. Pr o l if e r at i ve re t in o pa t h y is le ss p re va le n t , b ut ne ve r t h el es s is p re se n t
i n 30 % o f p e op le wi t h t yp e 1 d ia b et es an d i n 1 0 to 1 5% of in su l in - t re a te d p a t ie n ts wi t h t yp e 2
d i ab e te s wh o h a ve h a d di a be t es fo r ≥ 15 ye a rs . 7 , 9 , 2 6 4 , 2 65
P a t i en ts wi t h t ype 1 d ia be t es sh o ul d h a ve a di la te d r et i na l e xa m i na t io n wit h i n 3 t o 5 ye a rs of
d i ag n os is ; e va l ua t io n i s n o t n ec e ss ar y b e fo r e 1 0 ye a r s o f ag e . P a ti en t s wi t h t yp e 2 d i ab e te s
s h ou l d h a ve a c om p re h en s i ve e ye e xa m in a ti on so o n a f te r di a gn os is . Th e A D A r e co mm en ds
a n n ua l c om pr e he ns i ve eye e xa m i n at i on s . 5 , 73 , 265 L ess f r eq ue n t e ye e xa m s ( e ve r y 2 -3 ye a rs )
c a n b e c on si de r e d i np a tie n ts wi t h no r ma l e xa m s b a se d o n t h e a d vic e o f an
o p h th al m ol og is t . 26 5
C u r r e n t t he o ri es ad d r essi n g t h e p oss i bl e c au se s o f t hi s co mp l ic at i on ha ve b e en th o r ou gh l y
r e vi e we d . 2 64 Mi c r o vas cu l a r d is ea se ch a ra c te r i ze d b y th ic ke ni n g o f t h e ca p il l a r y m em b ra n e
m a y be t he un d er l yi ng les i on fo r t wo f o rms o f r e tin o p at h y. Th e f i rs t a n d mo s t c omm o n
p r e se n ta t io n i s a n o np r oli f e ra t i ve
P . 5 0 -7 8
r e t in o pa t h y c h a ra ct e ri zed b y mi cr o an e u r ys ms th at m a y p r o gr es s t o h a r d ye l lo w e xu d a t e s ,
s i gn i f yin g c h ro ni c l ea ka ge , r et i na l e d em a, an d p un c ta t e h em o r rh a ge . Th is f o rm o f r e ti no p at h y
m a y be as so ci a te d wi t h lo ss o f ce n t ra l vis io n , b ut g e ne r al l y is ass oc i at e d wi t h a n e xc e l l en t
vi s u al p ro gn os is . Fo ca l la s e r p ho t oc oa g ul a ti on o f t h e r e ti n a i n p at i en ts wi t h n on p ro l if e r at i ve
d i ab e ti c re ti n op a th y a nd m ac u la r ed em a d ec r ea s es t he li ke li h oo d o f vis ua l l os s b y 5 0% .
A s ec on d , l es s co mm on p r e se n ta t io n i s p ro l if e r ati ve r e ti n op a th y. Th is f orm is c h ar a ct e ri ze d b y
n e o vas cu l a ri za ti o n ( p r esu m ab l y du e t o re t in a l h yp o xi a ) a nd oc cu r s i n a ppr o xi m a t e l y 4 5 % o f
p e o pl e wi t h t yp e 1 di ab et e s a nd in 15 % o f pe op l e wi t h t yp e 2 di a be t es wh o h a ve h ad th e
d i se as e f o r 1 5 yea r s . N eo va s cu la r i za ti on ul t im a tel y l e ad s t o f i br os is , vi t reo u s h em o r rh ag e , a nd
r e t in a l d et a ch me n t. P ho to c oa g ul a ti on t he r ap y m ay a r r e st p ro g re ss i on an d d ec r e as e l oss o f
vi s i on ass o ci a te d wi t h ne o va sc ul a ri za t io n . 26 4 Be c au se h ype r t en si o n, smo k in g , u r em ia , a n d
h yp e r gl y c em i a ma y l ea d t o mo r e r a pi d p r og r es si on o f t h e r e ti no p at h y, e ver y e f f o rt sh o ul d b e
m a de to el im i na t e t he se r i sk fa c to r s f o r L . S.
Autonomic Neuropathy: Gastroparesis
H . D . i s a 36 - ye a r - o l d m a n w i t h a 20 - ye a r h i s t o r y o f t yp e 1 d i a be t e s. He i s i n po o r gl yc e m i c
c o n t r o l ( A 1 C , 1 2 %) a n d c o m pl a i ns o f f r e qu e n t, s e ve r e h yp o g l yc e m i c re a c t io n s t h a t d o n’ t
m a k e s en s e. Ac c o r d in g t o H . D . , “ I h a ve i n s ul i n r e a c ti o n s r i g ht a f te r I e a t , b u t la t e r o n , m y
g l u c os e c o nc e n t ra t i on s a r e sk y h i g h . ” H . D . p res e n t s t o th e d i a be t es cli n i c w i th a 2 - mo n t h
h i s t o r y o f n a u s e a, p os tp r a n d ia l fu l l ne s s, an d o c c as i on a l vo mi t i ng , all o f w h ic h a r e
u n r e l ie ve d b y a n t a c i d s . H . D . a ls o h a s p e r ip h e ra l n eu r o pa t h y i n vo l vi n g b o t h h is h an d s a n d
f e e t a n d m a ni f e st a t io n s o f a ut o n om i c n eu r o p a th y ( i m p o t e n ce an d o r tho s t a t ic
h yp o t e n s i o n ) . An u p p e r G I s e r ie s w as o r de r e d t o r u l e o u t p e pt i c u l ce r d i s ea se a nd r e fl u x
e s o ph a g it i s , b u t t h e p re l i m in a r y d i a g n o s i s w as d i ab e t ic ga s t r op a r es is . W ha t is t he ca u se
o f d i ab e t ic ga s t r op a r esi s ? H ow s h o ul d H . D. b e t r e a t ed ?
A u t o no mi c n eu r op a th y ma y p r es e nt as ga st r o pa r es is wi t h th e fe el i ng of fu ll n es s a nd na us e a,
u r i na r y r e te n ti o n, im po t en c e i n me n (m an i fe s te d a s re t r og r ad e e j ac ul a ti on o r an in a bi li t y t o
a t t ai n a n e r ec t io n ) , p os tu r a l h yp o te ns io n , t ac h yca r d ia , an d d ia r r he a wi t h i n co n ti ne n ce of
s t oo l . 2 6 6 Th e p re se nc e o f au t on om ic in su f f ic ie ncy m a y h a ve p r of o u n d e f fe c ts on th e p a ti e nt ' s
r e s po ns e t o vas o di la t in g d r u gs a n d a bi li t y t o c oun t e r ac t h yp og l yce mi a . 2 67
I m pa i r ed di ab e ti c c on t ro l wi t h “ u ne xp l a i ne d ” h yp og l yc em ia m a y r es ul t f rom t he di sr u pt e d
d e li ve r y o f f o od to t he int e s ti ne ; th a t is , gl uc os e d e li ve r y d oe s n o t co r r esp o n d wi t h p ra n di al
i n su li n a c ti on . Ma n y p a ti e n ts wi t h di ab e ti c g as t r op a r es is , l ik e H . D. , ha ve h a d d ia b e te s f o r ma n y
ye a r s a n d a ls o h a ve e vi de n ce of pe r i ph e ra l a n d au t o no mi c n eu r op a t hi es .
C o n ve n ti o na l a n ti em e ti c t h e r ap y is us ua l l y n o t h el p f ul in th e t r e at me n t o f g a st r o pa r es is .
P r o ki n et ic a ge n ts , s uc h a s m e to cl op r am i de , a r e c o ns id e re d fi r st - li n e t he ra p y. Me t o c lo p ra mi d e
i n c re as es gu t m o ti li t y t h ro u g h in d i re ct ch ol i ne r gi c s t im ul a ti on of t he gu t mu sc l e. H o we ve r ,
s ym p to ma t ic i mp r o vem en t do es no t al wa ys c or r el a t e wi t h im p ro ve d g as t r ic em p t yin g , wh i c h
i m pl ie s t h at th e ef f ec ti ven e ss o f m e to cl o p ra mi de a l so is d u e t o i ts ce n tr a lly m e di a te d
a n t ie me t ic a c ti vi t y. A u su a l s ta r t in g d os e o f m e toc l op r am id e i s 1 0 m g o r all y f o u r t im es da il y, 3 0
m i nu t es b e fo r e m ea ls and a t b ed t im e . A l th ou g h t re a tm e nt ma y n ot el im i nat e al l s ym pt om s , i t
s h ou l d mi ni mi ze mo st o f t h e p a ti e nt ' s c om pl a in ts . I f o ra l t h er a p y i s i ne f f ect i ve f or H . D . ,
m e to cl o p ra mi de ma y b e e f f ec t i ve i n e xt e m po r a neo u sl y co m po un d ed s u ppo s it o r y fo r m . O t h er
p h a rm ac o th e ra p eu t ic i n te r ve n t io ns in cl ud e d o mpe r i do n e ( n ot a vai l ab le in t h e Un i te d S ta t es ) ,
c is a p ri de ( wi t h d ra wn f r om t he U . S. ma r ke t ) , e r yth r o m yc i n, an d c ho l in e rg ic ag o ni st s . 2 6 8 Th e y
a r e re vi e we d b y V in ik and co l le ag u es . 26 7
Peripheral Neuropathy
S i x mo n t hs a f te r i ns t i tut i o n o f me t o c lo p r am i de 1 0 m g Q I D a n d s e ve r a l i n s ul i n
a d j us t m en t s , H . D . 's G I s ym p t o m s h a ve b e en all e vi a t e d, a nd h is di a be te s is n ow
r e a s on a b l y w e ll co n t r o ll e d as e vi de n ce d b y e l i m i n a ti o n o f h yp o g l yc e m i c e p i so d es an d a
r e c e n t A 1 C o f 7 .5 % ( n o r m a l , 4 % t o 6 %) . H o w e ve r , H . D . h a s b ee n co m pl a i n in g of i nc r e as i n g
b i l a te r a l fo o t a n d l e g pa i n , w hi c h h e d e sc r i bes a s a bu r n i ng o r a c hi ng s en s a ti o n . An
e x a mi n a ti o n o f hi s fe e t r e ve a l s c o ol ex t r e mi t i es w i t h a b se n t pu l se s an d l os s o f
m o n o fi l am e n t s en s a ti on . O u t l in e a p p r op r i a te s t e p s t h at ca n be t ak e n t o a ll e vi a te H . D . 's
p e r i p he r a l n e u r op a t h y.
D i a b et ic ne u ro p a th y ma y b e a co ns e qu en ce o f me t a bo li c d is t u rb an ce s i n t h e n e u ro ns ,
m ic r o an gi o pa t h y a f f ec ti ng t he ca pi l la r y su p pl y t o n e u ro ns , o r a n a ut o imm un e p ro ce ss . I t a f f ec ts
6 0 % t o 7 0 % o f t h e d ia bet i c p op u la t io n a n d h as a b r o ad sp ec t r um o f p r es en t a ti o n. C li n ic al l y, i t
m os t c om mo n l y p r es e nt s a s a di f fu se s ym me t r ic se n so r im o to r s yn d ro m e, a s ca r pa l t u nn e l
s yn d r om e, o r a s a ut o nom ic ne u r op a th y. S ym pt om a ti c d ia b et ic pe r i ph e ra l n e u ro pa t h y ( D P N )
o cc u rs in 25 % o f pa t ie n ts wi t h di ab e te s . I t i s ch ar a c te r i zed b y pa r es t he sia a nd pa i n in t he
l o we r e xt r e m i ti es th a t ma y b e m il d o r s e ve r e a nd u n r el en t in g ; d ec r ea se d s e ns at i on to
m o no f il am e nt te s ti ng ; dec r e as ed an kl e a n d kn e e j e r ks ; a nd de c re as e d n e rve c on d uc t io n
ve l o ci t y. Th e d ec r e as ed s e ns at i on as so ci a te d wi th p e ri ph e r al ne u ro p at h y c o nt r i bu t es t o th e
p r o g re ss io n o f fo o t i nj u rie s a n d i nf ec t io ns t ha t ma y g o u n no t ic ed b y th e pa t i en t u n ti l t h e y ar e
s e ve r e. 2 69 , 27 0 Th e m ana g em e nt of di a be t ic n e u ro p a th ie s h as be e n r e vi ewe d . 2 7 1
Simple Analgesics
P a i n fu l n eu r o pa t h y m a y r e s po nd t o si mp l e a na lge s ics ( e .g . , ac e ta mi n op he n ) or no n st e ro i da l
a n t i - i nf l amm a to r y d r ug s ( N S A I D s ) . Th e a na lg es ic s el ec t ed sh o ul d b e b as ed o n t he pa t ie n t 's
h i st o r y of r es po ns i ve ne ss t o t he se ag e nt s a s we l l a s t h ei r d u r at i on of ac tio n an d s id e -e f f ec t
p r o fi l es . Si de e ff ec t s i nc lu d e G I u ps et a nd bl ee d in g , a n d r e na l a nd he p at ic t o xi c it y.
Tricyclic Antidepressants
F o r pa in f ul ne u r op a th y th a t b ec om e s i nc ap ac i ta t in g an d i s u n re li e ve d b y s im p le an al g es ic s,
t r i c yc l ic a n ti d ep r es sa n ts ( TC A s ) c an be e ff ec t i ve a n d a r e t h e mo s t t ho r oug h l y s t ud i ed . TC A s
r e l ie ve pa i n b y in h ib i ti ng r e - up t ak e o f s e ro t on i n an d no r ep i ne p hr i ne ; b y a q u in i di n e - l ik e l oc al
a n al g es ic ef f ec t ; o r b y o th e r , a s ye t un e xp l a in e d, m ec h an is ms . Am it r ip t yl ine a nd im ip r am in e
a r e th e m os t c omm o nl y p r e sc ri b ed T C A s be ca use o f t h ei r fa vo r ab l e e ff e ct s on D P N . Da il y
d o se s t h at ha ve be e n use d ha ve be e n l o w t o m ode r a t e ( 25 t o 1 50 m g ) , a nd t he on se t of
a n al g es ia is e vid en t in 1 t o 4 we e ks ; us ua ll y d ose s o f 75 to 15 0 m g d ai l y a r e re q ui r ed f or
a d e qu a te pa in r el ie f . To m i ni mi ze s i de ef f ec ts , att e mp t s sh o ul d b e m ad e to us e
a n t id ep r es sa n ts al o ne .
P . 5 0 -7 9
Am i t r i p t yl i n e ( E l a vi l ) 25 m g a t be d t im e w as beg u n in H . D . w i th t he d os e t i t ra t e d t o 1 0 0 m g
a t b ed t i me o ve r 1 m on th . H . D . e x pe r i e nc e d m od e r a t e r e l ie f o f p ai n , a nd b o t h h is
p s yc h o l o g i ca l a n d s o ma t i c c o mp l a in t s o f de p re s s io n le s se n ed d ra m at i c a ll y. H o w e ve r ,
H . D . a ls o ex p e ri e nc e d in t o l e ra b l e c on s t ip a t io n, d r y m o u t h , an d u ri n a ry h e s i t a n c y.
At t e m p t s t o t a pe r t h e do s e o f am i t r i p t yl i n e w hi l e ma i n ta i ni n g p a in r e li e f w e r e
u n s uc c es s f ul . Wh a t o t he r d r u gs a r e e f fe c t i ve fo r t r e a t in g D P N ?
Mo s t o f th e ad ve r se ef f ec t s o f p s yc h ot r o pi c d ru g t h e r ap y ( se d at i on , a n ti cho l in e r gi c e ff e ct s,
e xt r a p yr a m i da l r e ac ti o ns, c ar d io va sc ul a r e f fe c ts ) a r e do se r el at e d e xc e p t fo r t a rd i ve
d ys ki n es ia . Pa t ie n ts wi t h a u to n om ic n e u ro p at h y an d th e e l de r l y ar e a t in c re a se d ri sk fo r
c om p li ca t io ns . Si nc e d esi p r am in e a n d n o rt r ip t yl ine a r e l ess li ke l y to ca us e s ed a ti o n,
a n t ic ho li n e rg ic s i de ef f ec t s, an d o r t ho st a ti c h yp ot e ns i on , we r ec om me n d th e i r p r ef e r en t ia l u se
o ve r am i t ri p t yli ne .
Anticonvulsants
Carbamazepine
F o r c as e s o f e xt r e m el y pa i n fu l D P N r es is t an t to si m pl e a na l ge si cs an d TCA s , c a rb am a ze pi n e
c a n b e t r ie d . D o se s h a ve va r i e d f r om 1 0 0 mg t hr ee t im es da il y t o 2 0 0 mg fo u r ti me s d ai l y.
D i zzi n e ss an d d r o ws in e ss a re co mm on bu t o f t en tr a n si en t , a n d G I di st u r ban c es o r
d e r ma t ol og ic r ea c ti on s ar e o bs er ve d in 5% to 10% o f p a ti en t s. C a rb am a ze p in e i s n o w r a r el y
u s ed be ca us e o f it s si d e e f f ec ts . Ph e n yt oi n ( D i la nt i n ) g e ne r al l y is n o t o f va l ue in t he t re a tm en t
o f di a be t ic n e u ro pa t h y be c au se t o xi c it y ( su ch as n ys t ag m us , a ta x i a , a n d se d a ti on ) o ft e n
d e ve l op s b ef o r e a t h e ra pe u t ic e f f ec t is se e n. Fu r th e r mo r e, ph e n yt oi n p o ten t i al l y de c re as es
i n su li n s ec r e ti on in t yp e 2 p at i en ts .
Gabapentin
G a b a pe n ti n ' s e xa c t m ech a ni sm of ac t io n i n t r ea t in g ne u ro p at h ic p a in is no t kn o wn , bu t i t m a y
b e th r o ug h i ts m o du l at i on o f c al ci um c h an n el s. 2 72 A r an d omi ze d , d o ub le -b l in d , p la ce b o -
c o nt r o ll ed 8 - we ek t ri a l eva l u a te d t h e us e of ga b ap e n ti n i n 1 65 p at ie n ts wi t h pa i nf u l d ia be t ic
n e u ro p at h y. 2 73 G ab a pen t i n wa s t it r a te d f r om 900 mg da i l y (d i vi de d TI D ) i n th e f i rs t we e k u p t o
3 , 6 00 m g d a il y ( d i vid ed TI D ) t o as se ss it s e f fi ca cy a n d to le r a bi li t y. G a ba pe n t in s i gn i fi ca n tl y
i m p ro ve d p ai n c om p ar e d t o pl ac eb o . Al th o ug h g ab a p en ti n wa s a ss oc i at e d wi t h m or e di zzi n es s
a n d s om no l en ce , o n l y 2 o f t he 84 pa t ie n ts t r e at ed wi t h ga b ap e nt i n wi t h d re w b e c au se o f si d e
e f f ec ts . Ba ck o nj a 2 7 2 r e vi e we d d at a f r om fi ve cl i ni c al t ri al s o f g a ba p en ti n a n d re co mm en ds a
s t a rt i ng do se o f g ab ap e nt i n o f 9 0 0 m g d ai l y (3 0 0 m g o n th e f i rs t d a y, 60 0 m g o n th e s ec on d
d a y, an d 9 0 0 m g d ai l y on t he t hi r d d a y ta ke n i n th r e e d i vid e d d os es ) ; t h e d o se s h ou l d b e
t i t r at e d t o 1 , 80 0 t o 3 , 60 0 m g /d a y fo r ef f ec t i ve r el ie f o f n eu r op a th ic pa i n. An a d van t ag e o f
g a b ap en t in is i t s l ack o f s i gn i fi ca n t d r ug in t er ac t io n s.
Other Anticonvulsants
L a mo t r ig in e a n d t op i r ama t e a r e n e we r a nt ic o n vuls a nt s t h at ha ve be e n f o un d to be e ff ec t i ve i n
p a in f ul di a be t ic n e u ro p a -t h y 1 65 , 2 74 , 27 5 L am o t rig i ne ca n b e s ta r t ed a t 25 t o 5 0 m g d ai l y an d
t i t r at e d b y 50 - mg in c re me n ts t o 4 00 m g d a il y; pa ti e n ts s ho u ld be c l os el y m o ni t o re d f o r r a sh .
To p i r a ma t e ca n b e s t ar te d at 25 mg da il y a nd inc r e as ed in 25 - mg in cr eme n ts t o 4 00 m g d a y
( t a ke n i n t wo t o th r e e d i vi d ed do s es ) .
Other Agents
A n o t he r an al g es ic , t r ama d ol , wh i ch bi n ds t o µ - op i oi d re ce p to r s a nd we ak l y in h ib i ts
n o r ep i ne p hr i ne an d s e rot o n in up t ak e, ha s b e en sh o wn t o be ef f ec ti ve in DP N . 2 7 6 , 2 77 P at i en ts
c a n b e s ta r t ed on 50 m g d a il y a nd t it r a te d i n 5 0 -m g i nc r em e nt s t o 4 0 0 mg d ai l y. I n on e c li ni c a l
t r i al , an a ve ra ge do s e o f 2 1 0 mg o f t r am ad ol wa s f o un d to be s i gn i fi ca n tl y m o re ef f ec t i ve t ha n
p l ac e bo i n t re a ti ng pa i nfu l di ab e ti c n eu r o pa t h y. 27 6
Th e a n ti a r rh yt h mi cs , m exi l e t i n e a nd li d oc ai n e, c an b e b en e fi ci al in t he t rea t me n t o f re si st a nt
n e u ro p at h y. 2 78 H o we ve r, b ec au s e o f i nc on si st e nt t h e ra p eu t ic b e ne f it s a nd a n i nc r e as ed ri sk of
s i de ef f ec ts , th es e a g en t s a re r es e r ved fo r c a se s t h a t c an no t be t re a te d su cc e ss fu ll y wi t h
o t h e r, le ss to xi c a ge n ts . Th e u se o f cl o ni di n e ( C at a p r es ) a ls o h as be e n s tu d ie d fo r th e
t r e a tm en t o f D P N b e ca us e p e r ip he r a l va so d il a ti on ma y d ec r ea se n eu r on al is ch em i a. I n t wo
c o nt r o ll ed st u di es , t r a nsd e r ma l c lo ni d in e r e su l ted i n r el i ef o f p ai n fu l d ia be t ic ne u r op a th y i n a
s u bp o pu la t io n o f pa t ie n ts . 27 1
To p i c al ap pl ic a ti o n o f 0 .0 7 5 % ca ps a ic in ( Zo st r i x) , t h e ac t i ve i ng r ed i en t i n h o t p ep p e rs , i s us e d
t o t re a t p os t he r pe t ic ne ur a l gi a a n d h as b e en r ec om me n de d f o r d i ab e ti c n eu r o pa t h y. Th is
n o n pr es c ri p ti o n p r ep a ra ti o n e nh a nc es th e re le a se a nd p re ve n ts th e r e ac cu m ul a ti on o f
s u bs ta n ce P i n n e r ve t e rm i na ls of t yp e - C n oc ic ept i ve fi b e rs . I n t h is wa y, i t i mp e de s t he
c o nd uc t io n a n d t r an sm iss i on of pe r i ph e ra l p a in im p ul se s. B ec au s e ca ps ai c in ac ts to de p le t e
s u bs t a n ce P f r om ne r ve f i b er t e rm in al s , in i ti a l h ig h le ve ls a re re l ea se d fro m th e f i be rs ,
r e s ul ti n g i n a bu r ni n g a nd s ti ng i ng s e ns at i on . H .D . s ho ul d be ad vi se d t h at b en e fi t f ro m
c a ps ai ci n m a y no t o cc u r f o r s e ve r al we e ks . Pa t ien t s s ho ul d u s e gl o ve s o r a n a p pl ic a to r to
a p pl y c ap sa ic i n a nd a void co n ta c t wi t h t he e yes or m uc ou s m em br a ne s . Ca p sa ic i n ma y b e
u s ef u l i n d ia be t ic pa t ie n ts in t ol e r an t o f o r a l me d ica t i on s. 2 71
Th e t r e at me n t o f D P N c on t i nu es to ce n te r on pr o vi d in g s ym pt om a ti c re li e f. Th e u se of
g a b ap en t in o r TC A s co n ti n ue s t o p r o vi de th e b es t a n al ge si c e f fe c t. A va ri et y o f ot h e r
m e di ca t io ns m a y p ro vi d e r e li e f i n r e f ra c to r y p at ien t s .
C a n a n yt h i n g b e do n e fo r H . D . ' s p e r ip h e ra l vas c u la r d is e as e ?
P e r i ph e ra l vas cu l ar di sea s e o r p e ri p he r al a rt e r ia l d is e as e ( P A D ) p re se n ts a s d im in is h ed o r
a b se n t f oo t pu ls es ( 35 % ), i nt e rm i tt e n t cl a ud ic a ti on ( 2 4% to 35 % ) , sk in ul ce r s , g an g r en e , o r
a m pu t at i on . Pe o pl e wi t h d i ab e te s a r e 2 to 10 ti mes mo r e l ik el y t o d e vel o p s ym p to ms o f P A D
t h a n t ho se wi t h o ut di a bet e s , a nd ha l f o f a ll no n t ra u ma t ic a mp u ta t io n s in th e U ni t ed S ta t es a re
p e r f o r me d i n p a ti e nt s wi th d ia be t es . In on e s tu d y t h a t f ol l o we d u p t ype 2 pa t i en ts f or 7 yea r s,
5 . 5 % h ad an am pu t at i on . Th e p r e val e nc e o f t hi s co n di t io n i nc r e as es wi t h ag e , d u r at i on of
d i ab e te s , a nd th e p r es e nc e o f ri sk fa c to r s su ch as h ype r t en si o n o r s mo kin g . 26 9 , 2 7 9
S i g ns an d s ymp t om s o f P A D i nc l ud e l eg pa i n, wh i ch is re li e ve d b y r es t ; c o ld fe e t ; n oc tu r n al l e g
p a in , wh i ch is re l ie ve d by d a n gl in g th e f e et o ve r t h e b e d o r wa lk i ng ; a bs en t pu ls es ; lo ss o f ha i r
o n th e fo o t a nd to es ; and g an g re n e. Tr e a tm e nt of t hi s c on d it i on i n cl ud es e l im in a ti o n a nd
t r e a tm en t o f ri sk fa c to r s s uc h a s sm o ki ng , d ys l ip id e mi a , h yp e rt e ns io n , a nd h yp e rg l yce mi a ;
a n t ip la t el e t t h er a p y; e xe r c is e , t he ma in s ta y o f t he r a p y; a n d r e vas cu l a ri zat i o n a nd s u r ge r y. 2 79
H . D . sh o ul d b e t h o ro u gh ly e d uc a t ed re g a rd in g p ro p e r f o ot c a r e a nd ha ve f r e q ue n t f oo t
e xa m i n a ti o ns . 2 8 0 , 2 81
P . 5 0 -8 0
S h o u l d L . S . b e s t a r te d o n as p i r i n t h e ra p y?
L . S . h a s se ve r al ca r di o va sc u la r ri sk fa c to r s ( mi cro a lb u mi nu r ia , d ys l ip id emi a , h yp t e rt e ns io n ,
o b es i t y, a nd ag e ) a n d sho u ld be st a r te d o n a sp i rin t he r a p y a s p r im a r y p r eve n t i on . Th e A D A
r e c omm e nd s as p i ri n t h era p y as se co n da r y p re ve nt i o n i n p at i en ts wi t h a h is t o r y of MI , va s cu la r
b yp a ss pr oc e du r e , P V D , s t r ok e o r tr a ns ie n t is c hem ic a tt ac k , cl a ud ic a ti on , a n d /o r an gi n a. 2 82
P r i ma r y p r e ven t io n i s i ndi c at e d i n i nd i vid u al s o ve r 4 0 yea r s o f a g e o r wh o h a ve ad d it i on al r isk
f a c to r s ( a f am il y h is t o r y o f C H D , s mo ki n g, h ype r te n si o n, al b umi n u ri a , d ysli p id em i a ). L. S .
s h ou l d t ak e a n e n te r ic -co a t ed as pi r in , 81 m g d a ily.
Drug-Induced Alterations in Glucose Homeostasis
P e r s on s wi t h di a be t es a re l ik el y t o t ak e m o re d rug s o ve r t he i r l if e ti me th an a n y o t he r g ro u p o f
p a t ie n ts . P a ti e nt s wi t h t yp e 2 d ia b et es p re se n t wi t h a c on st e ll a ti on o f ch r on i c co n di t io ns ,
i n cl ud i ng h ype r t en si o n, d ys l ip id e mi a, an d c a rd i ova s c ul a r d is ea se , a l l o f wh i c h a re am en a bl e t o
d r u g t h er a p y. D ru gs to ma n a ge de p re ss io n , i nt e rm i tt e n t in f ec t io ns , o b es ity, a n d n eu r o lo gi c a nd
o p h th al m ol og ic co nd i ti o ns al so a re co mm on l y p res c ri b ed . Be ca us e we kn ow t h a t t he ac t io ns of
d r u gs ar e c om p le x, a n d th a t fo r e ve r y d es i re d e f fe c t t h er e a r e s e ve ra l o t he r u n wa n te d e f fe c ts ,
e a ch ti me a d r ug is ad ded t o t h e r eg im e n o f s om eo n e wi t h d ia b et es , i t is im p o rt a nt to as se ss
t h e p a ti e nt ' s s i tu a ti on t o d e t e rm in e wh e th e r a po te n t ia l e xi s t s f o r a d ru g – dr u g i n t er ac t io n o r if
t h e b e ne f it o f t he ne wl y p r e sc ri b ed d ru g i s l ik el y t o ou t we i g h i ts ri sk s.
R e p r es e nt a ti ve d ru gs o r d r u g c la ss es th a t h a ve be e n re po r t ed to ca us e o r e xa c e r b at e
h yp e r gl yc em i a a nd h ypog l yc em ia a re li st e d i n Ta b l es 50 - 36 an d 5 0 - 37 , res p ec ti ve l y. Th e
s u bj ec t h a s b ee n r e vi e we d b y o t he r s . 2 83 , 2 84
Drug-Induced Hyperglycemia
Corticosteroids
A. L . , a 37 - ye a r - o l d o bes e w o ma n w i th s ys t e m i c l u pu s e r yt h e m a t o s us ( S L E ) , ha s b e en
t a k i ng 60 mg / d a y o f p r e d n i s on e fo r 6 m o n th s . D u r i n g t hi s p e r i od , he r w e ig h t h a s
i n c r ea s ed b y 3 0 l b a n d s h e h a s d e ve l op e d g l yc o s u r i a. S he w a s r e f e r r ed t o t he di a be t e s
c l i n ic , w he r e he r F P G w a s f o un d to b e 1 90 mg / d L ; t h e r e w a s 1 % g l u c o s e i n h e r u ri n e a n d
n o ke t o ne s . Ph ys i c a l ex a m in a t io n s h ow s a 5 ′2″ , 1 50 - l b, d ep r e ss e d w om a n w i th t r u nc a l
o b e si t y a n d a n a c ne i f o rm r a sh . H e r m o t he r an d o n e s i s te r ha ve d i ab e te s me l l it u s . H ow d o
c o r t i co s t e ro i d s c on t r i bu t e t o d i ab e te s m e l li t us ? H ow sh o u ld A. L . be t r e a t e d?
Th e t e rm st e r oi d d ia b et es wa s fi r st us e d t o d es cri b e t h e h yp e rg l yce mi a an d gl yc os u ri a s ee n i n
p a t ie n ts wi t h Cu sh i ng ' s syn d r o me . No w i t is as soc i at e d mo r e c om mo nl y w i t h e xo g e n o us l y
a d mi ni s te r ed gl uc oc o r ti co i ds an d h as be e n a s ide e f fe ct of p ar e nt e r al , o ra l , a n d e ve n t op ic a l
t h e r ap y. 2 85 C o rt ic os t e roi d s a r e o ne of th e m os t co mm o n d r ug g ro up s t h at u n ma sk l a te n t
d i ab e te s o r ag g ra va t e p re - e xi s t i ng di se as e , a nd th e y ma y p r od uc e h ype r gl yc em i a a nd o ve rt
d i ab e te s i n i nd i vi du a ls wh o a re no t o t he r wi s e p r ed i sp os e d.
C o r t ic os t e ro i ds i nc r e as e h e p at ic gl uc o ne og e ne si s a n d d ec r ea se ti ss ue r esp o ns i ve ne ss to
i n su li n . Al th o ug h s t er o id - i n du ce d d i ab e te s g en e ra l l y is m il d a n d r a re l y ass oc i at e d wi t h
k e to n em ia , a wi d e s p ec t ru m o f s e ve r it y ma y b e en c ou n te r ed — f r om a s ympt o ma t ic , a b no r ma l
g l uc os e t o le r an c e t es ts to d if f ic ul t - to - co n t ro l , i nsu l in - r eq u i ri ng di se as e . Th e on se t o f gl uc os e
t o l er a nc e c an occ u r wi t hin h ou r s t o d a ys o r a f te r m o nt hs t o ye a rs o f ch r oni c th e ra p y. Th e
e f f ec t g e ne r al l y is c o ns id e r ed do se d ep en d en t an d us ua ll y i s r e ve rs i bl e u p o n di sc o nt i nu a ti on o f
t h e d r u g; r e ve rs al m a y ta k e se ve r a l mo n th s . 2 8 3 , 2 8 6
A . L . e xh i b i ts ma n y s ym pt o ms th a t c an be at t r ib u te d to su p ra p h ys i ol o gi c do s es o f
c o r ti co s te r oi ds : tr u nc al ob e si t y, de p re ss io n , a n ac n ei f o rm ra sh , a n d d ia b et e s . Mi l d di a be t es in
o b es e i n di vi du a ls , a s i n A . L . ' s c as e, so me t im es ca n be c o nt r o ll ed b y di e t, b u t m a y r eq ui r e
t r e a tm en t wi t h a n ti di a be ti c m ed ic a ti o ns . A p er so n wi t h d ia b et es p ri o r t o g lu c oc o rt ic o id us e,
wh o s e co nd i ti o n is ag g r ava t e d b y u se of a g lu co co r t ic oi d , s ho u ld m o di f y t re a tm e nt
a p p ro p r ia t el y t o r es t o re g l yc em ic c o nt r ol . It is i mp o r t an t t o a n ti ci p at e th e n e e d t o mo d if y
i n su li n o r o ra l a n ti di a be t ic t he r ap y a s co r t ic os te r oi d do se s a r e i nc r ea se d or d ec r ea s ed .
Sympathomimetics
R . C . , a 4 1 - ye a r - o l d m a n w i th t yp e 1 d i a b e te s , is w e l l c o n t ro l l ed on s pli t d o se s o f r eg u la r
a n d N P H i n s ul i n a n d h as b ee n ta k i ng ps e ud o ep h e d r in e 3 0 m g Q I D fo r 7 d a ys a n d
R o b i t u ss i n D M 1 0 m L QI D (w h i c h c on t a in s 2 . 9 2 g m /5 m L s ug a r ) fo r a co l d . Re c en t l y,
g l u c os e c o nc e n t ra t i on s h a ve b ee n h i g he r t ha n u s u al . C an p se u do e ph ed r i n e o r t h e c ou g h
p r e p a r at i o n b e t h e c a us e o f h i s p oo r g l yc e m i c c o n t r ol ? D is c us s th e us e o f
s ym p a t h o m i me t ic s an d c o u g h p r e pa r a t io n s i n p a t i en t s w i th d ia b et e s.
O TC d r u g p r od uc ts , s uc h a s d ec o ng es t an ts an d di e t a i ds , wh i c h c on t ai n sym p a th om im e ti cs
c a r r y wa r n in g l a be ls th a t c au t io n a g ai ns t th ei r use i n p at i en ts wi t h di ab e te s . St a nd a rd s u ga r a n d e t ha n ol -c o nt a in i ng co u g h p re p a ra t io ns al so ca r r y s uc h wa r n i n g l ab el s. H o we ve r , cl i ni ca ll y
s i gn i fi ca n t d r ug - in d uc ed g l uc os e i n to l er a nc e p r oba b l y is ve r y i n f re q ue n t. It i s we l l es ta b li sh ed
t h a t p a re n te r al l y ad mi n ist e r e d e pi ne p h ri ne in c re as es bl o od gl uc os e c on c en t r a ti o ns s ec on d a r y
t o in c re a s e d g l yc o ge n ol ys is an d g l uc on e og e ne si s. O t h e r s ymp a th om im e ti cs ge n e ra ll y d o n o t
h a ve as po t en t a n e f fe c t o n bl oo d gl uc os e a s e pi ne p h ri n e, an d th ei r us e us u al l y do es no t p o se
a p r ac ti ca l p r ob l em i n d ia b e ti c p at i en ts . N e ve rt he l es s, t he r ap e ut ic t o h igh o r al d o se s o f
p h e n yle ph r i ne c a us ed h yp e r gl yc em ia an d a c et o nur i a i n th r ee no n di a be ti c ch i ld r e n. 2 87 , 28 8
F u r t he r mo r e, t he ef f ec ts o f s ym p at h om im et ic s o n B P m us t b e c on si d er e d in ma n y pa t ie n ts wi t h
d i ab e te s . Th e r e fo r e , we r e c omm e nd an t ih is t am ine s o r oc ca si on a l us e o f n a sa l s p ra ys fo r
s e ve r e co n ge s ti on .
I n su mm a r y, ps e ud o ep h ed r i ne o r t he co ug h pr e par a t io n m a y be ag g r a vat i n g R . C . ' s d ia b et ic
c o nt r o l, al t ho u gh at th e se l o w t o n o rm al th e r ap e ut i c d os es it is q u it e u n li ke l y. Th e s t r ess
r e l at e d t o R. C . ' s u n de r l yi n g c ol d i s mo r e l ik el y t o b e i mp a ir i ng hi s g lu co se t o le r a nc e t ha n t h es e
l o w d o se s o f s ym pa t ho mi m et ic ag e nt s o r th e sm al l am ou n ts o f s u ga r c o nta i ne d i n th e c ou g h
s yr u p .
Drug-Induced Hypoglycemia
Ethanol
C . F . , a 22 - ye a r - o l d w o ma n w i t h n ew l y d i a g n o s ed t yp e 1 d i ab e t es , e n j oys a g l a s s o r tw o of
w i ne w i t h h e r e ve n i n g m e a l. W ha t e f f e ct d oe s a l c oh o l h a ve o n a p a t ien t w i t h di a be t es ,
p a r t i cu l a r l y
P . 5 0 -8 1
o n e us i ng i ns u l in ? Is alc o h o l c on t r a i nd i ca t e d in C . F . o r a n y p e r s o n w it h d i ab e te s ?
Table 50-36 Drugs That Can Increase Blood Glucose Levelsa,b
Drug/Class Name
Clinical
Significancec Comments
Asparaginase
++
Generally resolves during or after asparaginase
therapy is completed. Concomitant corticosteroids
may increase the incidence and severity of glucose
intolerance.
Atypical
antipsychotic agents
+++
Cause hyperglycemia and new-onset type 2
diabetes (reported with olanzepine and clozapine)
β2-Agonists
++
Can induce maternal hyperglycemia when used as
a tocolytic. For effect on infants, see Table 50-37.
β-Adrenergic
blockers
++
Alternative antihypertensive therapy preferred,
unless the benefits outweigh the risks (i.e.,
prevention of second myocardial infarction).
Cardioselective α-blockers may cause fewer
adverse effects than nonselective agents.
Calcitonin
+
Few case reports.
Calcium antagonists
+
Do not appear to cause clinically significant longterm adverse effects on carbohydrate metabolism.
Carbamazepine
+
One known case report.
Cimetidine
+
Few case reports.
Corticosteroids
+++
Glucose intolerance can occur within hours to
days or after months of chronic therapy. The
adverse effect generally is considered dose
dependent and reversible upon discontinuation; the
reversal may take several months.
Cyclosporine
++
May cause hyperglycemia and require insulin
therapy during long-term therapy, whether or not
concomitant corticosteroids are part of the
immunosuppressant regimen.
Diazoxide
+++
Causes hyperglycemia predictably in most
patients. Oral formulation used as therapeutic
glucose-elevating agent.
Didanosine
+
Hyperglycemia without pancreatitis possible.
Diuretics
+++
All classes of diuretics, and in particular thiazides,
have been reported to cause diabetes mellitus or
worsen glucose control in people with diabetes;
some may tolerate low doses (25 mg hydrochlorothiazide equivalent).
Encainide
+
Two known reports in the biomedical literature.
Imipramine
+
Few case reports.
Isoniazid
+
Few case reports.
Lithium
+
Conflicting data in the biomedical literature.
Marijuana
++
One case required 3-fold increase in insulin dose;
another developed diabetic ketoacidosis after
ingesting large amounts orally. δ-9tetrahydrocannabinol impaired glucose tolerance
in six subjects (6 mg IV).
Megestrol acetate
+
Few case reports.
Nicotinic acid
++
Alternative agents for hyperlipidemia preferred for
people with diabetes. See Question 81.
Oral contraceptives
++
Appears to occur less frequently with an estrogen
dose <50 µg.
Pentamidine
+++
Diabetes mellitus may occur days after initiation
of therapy, but more often is delayed by several
weeks or even months. Initially, pentamidine may
cause hypoglycemia (see Table 50-37).
Phenothiazines
+
Many case reports, most involving
chlorpromazine. Controlled studies lacking.
Phenytoin
++
Predisposed individuals (family history,
underlying insulin resistance, high doses) may
develop hyperglycemia. Overall incidence very
small.
Pravastatin
+
One known case report.
Protease inhibitors
+++
Many cases of new-onset diabetes or worsening
diabetes reported to the FDA. Some cases required
hospitalization and were irreversible. Related to
lipodystrophy and insulin resistance.
Rifampin
+
Few case reports.
Sympathomimetics
++
Clinically significant hyperglycemia infrequent,
especially at usual doses.
Tacrolimus
++
May cause hyperglycemia and require insulin
therapy during long-term therapy, whether or not
concomitant corticosteroids are part of the
immunosuppressant regimen.
Thyroid hormones
+
Adverse effect at excessive doses.
a
The authors acknowledge Joanne M. Yasuda, Pharm D, who updated this table using
primary references.
b
This table does not include the many drugs that interact with the drugs used to treat
diabetes (e.g., sulfonylureas).
c
Clinical significance:
+ Clinical significance possible. Limited or conflicting reports or studies.
++ Clinically significant. Primarily important under certain conditions.
+++ Clinically significant effect of substantial prevalence and/or magnitude.
Adapted from reference 284.
C l i ni ci a ns of t en a re re l uc t an t to pe r mi t t h e u se of a lc oh o li c b e ve ra ge s i n p a t ie n ts wi t h
d i ab e te s . H o we ve r , b ar r in g c o nt r a in di ca t io ns t ha t a r e s im il a r i n t he n on di ab e t ic a n d d ia b et ic
a l ik e ( e . g. , a lc o ho li sm , hyp e r t r ig l yce r i de mi a , g as tr i t is , p a nc r ea t it is , p r e gna n c y) , a pe rs o n wi t h
d i ab e te s c an sa f el y e nj oy a m od e ra t e a lc oh o l i nta k e as lo n g a s ce r t ai n p re c au t io ns a re ta ke n .
F o r an in - de p th di sc us sio n , th e r e ad e r i s r e fe r r ed t o t wo c om p re h en si ve r e vi e ws o f a lc oh o l a nd
d i ab e te s , p a rt s o f wh ic h a r e s um ma r i ze d i n t he fol l o wi n g l is t . 2 89 , 2 90
P . 5 0 -8 2

D r i n k i n mo d e ra ti o n . Th e A D A d e fi ne s t hi s a s a da i l y in t ak e o f o ne d ri nk fo r a du l t
wo m e n an d t wo d ri nk s f or a d ul t m en ( 5 o z wi n e , 12 o z be e r , 1 . 5 o z di st i ll ed l iq uo r ) . Th e
p a t ie n t sh o ul d b e a wa r e o f hi s o r h e r o wn s e ns it ivi t y t o th e i n to xi c a t in g e ff e c ts o f
e t h an ol a nd ad ju s t co nsu m pt i on do wn wa r d , i f n ee d e d. Th is is pa r ti cu l a rl y i mp o r ta n t f o r
i n su li n - de pe n de n t p a ti ent s . W hen ha vi n g a d r in k , b e s u r e t o h a ve i t wi t h a m e al .
Table 50-37 Drugs That Can Decrease Blood Glucose Levelsa,b
Drug/Class Name
Clinical
Significancec Comments
Anabolic steroids
+
Complex metabolic effects. Only certain
steroids studied.
Angiotensinconverting enzyme
(ACE) inhibitors
+
May increase peripheral sensitivity to
insulin effects. Two case reports and one
case-control study.
β-Adrenergic
blockers
++
β-Blockers may prolong and mask the
symptoms of hypoglycemia.
Cardioselective β-blockers may cause less
adverse effects than nonselective agents.
β2-Agonists
++
Can induce hypoglycemia in the infants of
mothers who received these agents for
tocolysis. For effect on mother, see Table
50-36.
Disopyramide
++
Elderly patients with liver and/or renal
impairment appear to be the most
susceptible to this serious adverse effect.
Ethanol
+++
Most often occurs in individuals
chronically drinking large amounts of
ethanol. The adverse effect can follow
binge drinking and even moderate alcohol
intake in fasting individuals. Symptoms of
hypoglycemia may be mistaken for
intoxication.
Insulin
+++
Injectable solution or suspension used
therapeutically to decrease glucose levels
in people with diabetes.
Pentamidine
+++
Usually occurs several days to 2 weeks
following initiation of therapy. It can be
sudden, recurrent, and life-threatening.
Pentamidine also may cause
hyperglycemia (see Table 50-36).
Quinine/quinidine
++
Quinine 600–800 mg Q 8 hours for
malaria may induce hypoglycemia in 10%
of patients. Doses of 300 mg for leg
cramps produce hypoglycemia
infrequently.
Salicylates
++
Occurs with salicylate intoxication or antiinflammatory doses (4–6 g/day in adults).
Low doses unlikely to cause this adverse
effect.
Sulfonamides
+
Rare reaction with renal failure and/or
high doses.
Sulfonylureas
+++
Oral hypoglycemic agents used
therapeutically to decrease glucose levels
in people with type 2 diabetes.
a
The authors acknowledge Joanne M. Yasuda, Pharm D, who updated this table
using primary references.
b
This table does not include the many drugs that interact with the drugs used to treat
diabetes (e.g., sulfonylureas).
c
Clinical significance:
+ Clinical significance possible. Limited or conflicting reports or studies.
++ Clinically significant. Primarily important under certain conditions.
+++ Clinically significant effect of substantial prevalence and/or magnitude.
Adapted from reference 233.

A vo i d dr i nk s t ha t c o nt ai n l a rg e am ou n ts o f s u ga r , s uc h a s l iq ue u rs , s we e t wi n e s , a n d
s u ga r - co n ta in i ng m i xe s . I n s te ad , c o ns id e r d r y wi n e s, li g ht be e rs , a n d d is ti l le d s pi r i ts .
N o t on l y d oe s t he sim p le s ug a r c on t en t ad d a n a dd i t io na l s ou r ce o f g lu co se a nd
c a lo r ie s t o t h e d ie t , b u t e t h an ol in g es t ed wi t h s im p le s u ga r –c o nt ai n in g mi xe r s e n ha nc es
r e a ct i ve h yp e r gl yc em ia .

R e m em be r to co u nt th e c a lo r ie s i n a lc oh o l ( ca l ori e s = [0 . 8] × [ p r oo f ] × [oz] ) ; s ub st i tu t e
1 o z o f a lc oh ol f or t wo f at e xc h a n ge s.

B e a wa r e th a t t h e s ymp to ms o f a lc oh ol in t o xi c a tio n an d h yp o gl yc em ia a re s im i l a r . I f
h yp o g l yc em i a is mi st ak en f o r i nt o xi c a ti o n b y o th er s , a p p ro p ri a te an d p o ten t i al l y li fe s a vi ng t re a tm en t c a n b e d e la ye d .

B e a wa r e of al co h ol –s ul fo n yl u re a d r u g i nt e ra c ti ons , s p ec if ic a ll y t he al co h ol - i nd uc e d
e n zym e i n du c ti on o f t ol bu t am i de m e ta b ol is m a nd t h e c hl o r pr o pa mi d e – al coh o l f l us h
r e a ct i on .
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D i a b et es Me l l i tu s, 5 th Ed . S ta m fo r d , C T: A p pl e ton & La n ge , 1 9 97 : 48 7 .
1 6 . Tu r ne r R e t al . U K PD S 2 5 : a u to an t ib o di es to i sl e t -c el l c yt op l asm an d g l u ta mi c ac i d
d e ca r bo xyl a s e f o r p r ed ict i o n o f i ns ul i n r eq u i re men t in t yp e 2 d i ab e te s. U K P r o sp ec t i ve
D i a b et es S tu d y G r o up . La n ce t 1 9 97 ; 35 0 :1 2 88 .
[ C r o ss R e f]
1 7 . Am e ri ca n Di a be t es As so ci a ti o n ( A D A ) P os it i on S t at e me n t. G es t at i on a l D i a be t es Me l l it us .
D i a b et es C a re 20 0 4; 2 7 (S u p pl 1 ): S 8 8.
1 8 . A D A . Th e E xp e r t C om mi t t ee on th e Di a gn os is an d Cl a ss if ic a ti o n o f D i a be t es Me l l i tu s:
f o l lo w- u p r ep o r t o n t he di a gn o si s o f d ia b et es m e lli t us . D ia be t es C a re 20 0 3; 2 6 :3 1 60 .
1 9 . G o ra n MI e t a l . O b esi t y a nd r isk o f t yp e 2 di ab e t es a n d c ar d io va sc ul ar d is e as e i n ch i ld r en
a n d a d ol es ce n ts . J Cl i n E n d oc r in o l Me t a b 20 0 3; 88 : 1 41 7 .
[ C r o ss R e f]
2 0 . St r a t to n I M e t a l . A ss oc i at i on of gl yc ae mi a wi t h m ac r o vas cu la r an d mi c r o vasc u la r
c om p li ca t io ns of t yp e 2 di a be t es ( U K P D S 3 5 ) : p r os p ec ti ve o bs er va t io n al s tu d y. B r Me d J
2 0 0 0; 3 21 : 40 5 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 1 . Th e e f fe ct o f i nt e ns i ve t r ea tm e nt o f d ia be t es o n th e d e ve lo pm e nt an d p r o g re ss io n o f l o ng t e r m co m pl ic at i on s i n i nsu l in - d ep en d en t di ab e te s m e ll i tu s. Th e D ia be t es Co n t r ol an d
C o m pl ic a ti o ns Tr i al R ese a r ch G r ou p . N E n gl J Me d 19 9 3; 3 29 : 97 7 .
2 2 . In t en si ve bl oo d - gl uco s e co n t ro l wi t h s ul ph o nyl u r e as or in s ul in c o mp ar e d wi t h c on ve n ti o na l
t r e a tm en t a n d r is k o f c om p li ca t io ns in pa t ie n ts wi t h t yp e 2 d ia be t es ( U K PD S 3 3 ) . U K
P r o s pe ct i ve Di a be t es S tu d y ( U K P D S ) G r ou p . L anc e t 1 99 8 ;3 5 2: 8 37 .
2 3 . G ae d e P H et al . [ Th e S t e no - 2 s tu d y. In t en si ve m ul t if a ct o ri a l i nt e r ve nt ion r e du ce s t he
o cc u r r en ce of ca r di o vasc u la r di se as e i n p a ti en t s wi t h t yp e 2 di a be t es ] . Ug e sk r L a eg e r
2 0 0 3; 1 65 : 26 58 .
[ Me d l i n e L in k ]
2 4 . A D A . A me r ic an D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. Sc r e en in g fo r t yp e 2 d i ab e te s .
D i a b et es C a re 20 0 4; 2 7 (S u p pl 1 ): S 1 1.
2 5 . Ka kk a R, K od a - Ki mb le MA . C a n i ns u l in t he r apy d e l a y o r p re ve n t i ns ul in - d ep e nd e nt
d i ab e te s m el li t us ? Ph a rm ac o th e r ap y 1 99 7 ;1 7 :3 8.
2 6 . Sc ha t z D A , Bi n gl e y P J . U pd a te on m a jo r t ri als f or t he p re ve n ti on o f t yp e 1 d ia b et es
m e ll i tu s: th e Am e ri ca n Di a be t es P r e ven t io n Tr ia l ( D P T - 1 ) a n d t h e E u ro p ea n N ic ot i na mi d e
D i a b et es I nt e r ven t io n Tr ia l ( E N D I T) . J P ed ia t r End o c ri no l Me t a b 2 00 1 ;1 4 (S u p pl 1 ): 6 19 .
2 7 . Ef f ec ts o f i ns ul in in re l a ti ve s o f p a ti en t s wi t h t yp e 1 d ia b et es me ll i tu s . N E n gl J Me d
2 0 0 2; 3 46 : 16 85 .
2 8 . G al e E A. In t e r ven i ng b e fo r e t h e o ns e t o f Ty p e 1 d i ab e te s: ba s el in e da t a fr om t he E ur o pe a n
N i c ot i na mi d e D i ab e te s In t e r ve nt i on Tr i al ( E N D I T) . D i ab e to l og ia 20 0 3; 4 6:3 3 9 .
[ C r o ss R e f]
2 9 . He r o ld K C e t al . An t i - C D 3 mo n oc lo n al an t ib od y i n n e w - o n se t t ype 1 di a be t es m e ll i tu s. N
E n g l J Me d 20 0 2; 3 46 : 169 2 .
[ C r o ss R e f]
3 0 . Kn o wl e r W C e t a l . Re d uc t io n i n t h e i nc id e nce o f t yp e 2 di a be t es wi t h l i fe st yl e i n te r ve n ti o n
o r me t fo r mi n . N E n gl J Me d 20 0 2; 3 46 : 39 3 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
3 1 . Fo n tb on n e A e t al . Th e ef f ec t o f m e tf o rm i n on t he me t ab ol ic ab n o rm al i ti e s as so ci a te d wi t h
u p p er - b od y f a t di s t ri bu t io n . BI G P R O S t u d y G r oup . D ia b et e s C a r e 1 99 6 ;19 : 9 20 .
[ C r o ss R e f]
3 2 . Ef f ec ts o f wi t h d r a wa l f r om me t fo r mi n o n t h e de ve l o pm en t o f d i ab e te s in t he di a be t es
p r e ve n ti on p ro g r am . D i ab e t es C ar e 2 0 03 ; 26 : 97 7 .
3 3 . Tu om il e ht o J et al . P r e ve n t io n o f t yp e 2 d ia bet e s m el li t us b y c ha n ge s in l if es t yl e a mo ng
s u bj ec ts wi t h im pa i re d g lu c os e t ol e r an ce . N En gl J Me d 2 00 1 ; 34 4 :1 34 3 .
[ C r o ss R e f]
3 4 . Ch i as so n J L e t a l. Ac a r bo se fo r p re ve n ti on of t yp e 2 di a be t es m el l it us : th e S TO P - N I D D M
r a n do mi se d tr i al . L a nc et 2 0 0 2; 3 59 : 20 72 .
[ C r o ss R e f]
3 5 . Bu ch a na n TA e t al . P r e s er va t io n o f pa nc r ea ti c b e ta - ce l l f un ct i on an d p r e ve n ti on o f t yp e 2
d i ab e te s b y p ha r ma co l ogi c al t re a tm en t o f in su li n r e s is ta nc e i n h i gh - r isk his p an ic wo m en .
D i a b et es 20 0 2; 5 1: 2 79 6 .
[ C r o ss R e f]
3 6 . Fr a n z MJ e t a l . N u t rit i o n p ri n ci pl es an d re com me n da t io ns in di a be t es. D i ab e te s Ca r e
2 0 0 4; 2 7( S u pp l 1 ) : S3 6 .
3 7 . Fr a n z MJ . Me d i ca l Nu t r i ti on Th e r ap y. I n: F ran z MJ , e d . D ia be t es Ma n a g em e nt Th e r ap ie s ,
4 t h Ed . C hi ca go : Am e ri ca n As so ci a ti o n o f Di ab e te s Ed uc a to r s , 2 00 1 :3 .
3 8 . G r ue ss ne r A C , S u th er l a nd D E . Pa nc r ea s t r a ns p la n t o ut co m es f o r Un i te d S ta t es ( U S ) a nd
n o n - U S c as es a s re po r t ed t o t h e U n it e d N e t wo r k fo r O r g an S ha r in g ( U N O S) a n d t he
I n t e rn a ti o na l P a nc r ea s Tr a n sp la n t Re gi s t r y (I P TR ) a s o f Oc t ob e r 2 00 2 . Cl in Tr a n sp l 2 0 02 : 41 .
3 9 . Ro b e rt so n R P e t a l . P a n c re as t ra ns p la n ta ti o n f o r p a ti e nt s wi t h t yp e 1 d i ab e te s . D i ab e te s
C a r e 20 0 4; 2 7( S u pp l 1 ) : S1 0 5 .
4 0 . Sh a pi r o A M e t a l . I sle t t ra ns p la n ta t io n i n s e ve n pa t ie n ts wi t h t yp e 1 di a be t es m e ll i tu s us i ng
a g lu co co r t ic oi d -f r e e imm u no su p p re ss i ve r e gim en . N E ng l J Me d 20 0 0; 3 43 : 2 30 .
[ C r o ss R e f]
4 1 . O be r ho l ze r J et al . Cu r r e nt st a tu s o f i sl e t ce l l t r a ns pl a nt a ti o n. A d v Su rg 2 00 3 ;3 7 :2 5 3.
[ Me d l i n e L in k ]
4 2 . G ol ds t ei n D E e t a l . Am e r ic an D ia b et es As so cia t i on P os it i on S ta t em en t. Te s ts o f g l yc em i a
i n di ab e te s . D i ab e te s Car e 2 00 4 ;2 7 ( Su p pl 1) : S 91.
[ Me d l i n e L in k ]
4 3 . Ro h lf i ng C L e t a l . D ef i n in g t h e r el a ti o ns hi p b et we e n p la sm a g lu co se an d H b A (1 c ): an a l ys is
o f gl uc os e p r o fi l es a n d Hb A ( 1 c) in t he D ia b e t es Co n t r ol an d Co mp li ca t io n s Tr i a l . Di a be t es C ar e
2 0 0 2; 2 5: 2 75 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
4 4 . A D A . S t an da r ds o f me d ic al ca r e f o r p a ti en t s wi t h d i ab e te s m el li t us . Di a be t es C a re 20 0 4; ( 27
S u p pl 1 ): S 1 5.
4 5 . Ce r i el lo A e t al . Vi t am i n E r ed uc t io n o f p r o te in g l yc os yl a ti o n i n d ia b ete s . Ne w p r o sp ec t fo r
p r e ve n ti on o f d ia be t ic c om p li ca t io ns ? Di a be t es Ca r e 19 91 ; 14 : 68 .
4 6 . Da vi e SJ et al . E ff ect o f vit am i n C o n gl yc os yl a t io n o f p r o te in s . D i ab e te s 1 9 92 ; 41 : 16 7 .
[ C r o ss R e f]
4 7 . No l te MS , K a r a m, J.H . P a nc r ea t ic H o rm on es & A n t id ia b et ic D r ug s . I n : K a t zu ng B , e d . B as ic
a n d Cl i ni ca l P h a rm ac ol og y, 8 t h E d . N e w Yo r k : L an g e Me d ic a l B o o ks / Mc G r a w H i l l , 2 0 01 : 71 1 .
4 8 . De F el i pp es M e t a l. In s ul in C h em is t r y a n d P ha r m ac ok in e ti cs . I n : P o r te D S , R S , Ba r o n A ,
e d s. E ll e nb e rg an d Ri f kin ' s D ia b et es Me l l i tu s , 6 th E d . N e w Yo r k : Mc G r a w - H i l l, 20 0 3 :4 81 .
4 9 . Va n Ha e f te n TW . Cl in i ca l s ig ni f ic an c e o f i ns ul i n a n ti bo d ie s i n i ns ul in - tr e a t ed di ab e ti c
p a t ie n ts . Di ab e te s Ca r e 1 9 8 9; 1 2: 6 41 .
[ C r o ss R e f]
5 0 . Bi n de r C , B r a ng e J . In s ul in ch em is t r y an d p h ar m ac ok i ne t ics . In : Po r t e D , J r , S h e r wi n R,
e d s. E ll e nb e rg ' s a n d R i fk i n 's D ia b et es Me l l i tu s , 5 t h Ed . S ta mf o r d, C T: Ap p le t on & La ng e ,
1 9 9 7: 6 89 .
5 1 . Ra b ki n R e t a l. Th e re n al me t ab ol is m o f i ns u lin . D ia b et o lo g ia 19 84 ; 27 :3 5 1 .
[ C r o ss R e f]
5 2 . Bu r g e MR , S c h a de DS . I ns ul i ns . En do c ri n ol Me t a b C l in N o rt h Am 19 97; 2 6 :5 7 5.
[ C r o ss R e f]
5 3 . Ho l le ma n F e t a l. R ed u ce d f r e qu e nc y of se ver e h yp og l yce mi a a n d com a i n we l l -c on t ro l le d
I D D M p a t i e n ts t re a te d wit h in su l in li sp r o. Th e B en e lu x - U K I n s u li n L is p ro S t u d y G r o up . Di a be t es
C a r e 19 9 7; 2 0: 1 82 7 .
[ C r o ss R e f]
5 4 . Ra sk i n P et al . A c om p a ri so n o f i ns u li n l is p ro a nd bu f fe r e d r e gu la r hu m an in su li n
a d mi ni s te r ed vi a c on t in uo u s su b cu t an eo u s in s ul in i nf us i on pu mp . J D ia b et e s Co mp li c at io n s
2 0 0 1; 1 5: 2 95 .
[ C r o ss R e f]
5 5 . He is e T e t a l. Ti m e - ac t io n p r o fi le s o f n o ve l p re m i xe d p re pa r a ti o ns o f in s ul in li sp r o a n d N P L
i n su li n . Di ab e t es Ca r e 19 9 8 ;2 1 :8 0 0.
[ C r o ss R e f]
[ Me d l i n e L in k ]
5 6 . Bo l li G B , O we n s D R . I n su li n g l ar g in e . L an ce t 2 0 0 0; 3 56 : 44 3 .
[ C r o ss R e f]
5 7 . L e po r e M e t al . Ph a rm ac o ki ne t ic s a nd ph a rma c od yn am ic s o f s ub cu t an e o us i nj e ct i on of
l o ng - ac t in g h um a n i ns ul in a na lo g gl a rg in e , N P H in s ul in , an d u l t ra le n te hum a n i ns ul in an d
c o nt i nu o us s ub cu t an e ous in f us io n o f in su li n l is p ro . D ia b et e s 2 00 0 ;4 9 :2 142 .
[ C r o ss R e f]
5 8 . Du n n CJ e t al . I ns u lin g la r gi n e: an up d at e d re vi e w o f i ts u se in t he ma n a ge me n t o f
d i ab e te s m el li t us . D ru gs 2 0 0 3; 6 3: 1 74 3 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
5 9 . Am e ri ca n Di a be t es As so ci a ti o n ( A D A ) P os it i on S t at e me n t. Im pl ic a ti o ns o f t he D ia b et es
C o n t r ol an d Co mp l ic at i on s Tr i al . Di a be t es C ar e 2 0 0 3; 2 4( S u pp l 1 ) : S2 8 .
6 0 . W als h J , R o be r ts R . P u m pi ng I ns ul in , 3n d Ed. S a n D i eg o , C A: To r r e y P i n e P r es s , 2 00 0 .
6 1 . A D A . A me r ic an D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. C on t in u ou s s ub cu t a ne ou s i ns ul i n
i n f us io n . D i ab e te s C a r e 2 0 0 4; 2 7( S u pp l 1 ) : S1 1 0.
6 2 . A D A . R es o u rc e G u ide . D ia b et e s F o re ca st 200 3 ; J an u a r y.
6 3 . Pi ck up J, K ee n H . Co n t in uo u s s u bc u ta n eo us i n su li n i n fu si o n a t 2 5 yea r s : e vi de nc e b as e fo r
t h e e xp a n d i ng us e o f i nsu l in pu mp t he r ap y i n t ype 1 d i ab e te s. D ia b e te s Ca r e 20 02 ; 25 : 59 3 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
6 4 . Sa u de k C D . N o vel f or m s o f i ns ul i n d el i ve r y. En d oc r in o l Me t a b C li n N ort h Am 1 99 7 ;2 6 :5 99 .
[ C r o ss R e f]
6 5 . Hi r sc h I B . Im pl em en ta t i on of in t en si ve in su l in t h e ra p y fo r I D D M. D i a b et e s Re vi e w
1 9 9 5; 3 :2 8 8.
6 6 . L e nh a rd MJ , R e e ves G D . C o n t in uo us su bc u tan e o us i ns u li n i nf u si on : a c om p re h en si ve
r e vi e w o f in su l in pu mp the r a p y. A rc h I n te r n Me d 20 0 1 ;1 6 1: 2 29 3 .
[ C r o ss R e f]
6 7 . Ra t n er R E et al . L ess h ypo g l yc e mi a wi t h i ns ul i n g la r gi n e i n i nt e ns i ve in s ul in t he r ap y f o r
t yp e 1 d ia b et es . U . S . S tu d y G r o up o f I ns ul i n G l ar g i ne in Typ e 1 Di a be t es. D i ab e te s Ca r e
2 0 0 0; 2 3: 6 39 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
6 8 . G in H , Au be r t in J . Ge n e ra l i zed al le r g y du e to zi n c a nd p ro t am in e i n i ns u li n p r ep a r at i on
t r e a te d wi t h i ns ul i n p ump . D ia b et e s C a r e 1 98 7 ;10 : 7 89 .
[ Me d l i n e L in k ]
6 9 . A D A . A me r ic a n D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. In su l in ad mi n is t ra t io n . Di a be t es
C a r e 20 0 4; 2 7( S u pp l 1 ) : S1 0 6 .
7 0 . Ko i vis t o V A , Fe li g P . A l t e ra t io ns in in su li n a bs o r pt i on an d i n b lo o d g luc os e c o nt r ol
a ss o ci at e d wi t h va r yi n g in s ul in in j ec ti o n si t es in di a be t ic pa t ie n ts . A n n I n te r n Me d 1 98 0 ;9 2 :5 9 .
7 1 . Am e ri ca n Di a be t es As so ci a ti o n ( A D A ) . I n su li n a dm i ni st r a ti o n. D ia b et es C a r e 2 0 04 ; 27 ( S up p l
1 ) : S 12 1 .
7 2 . Yo u ng R J e t a l. D ia be t ic li p oh yp e r tr o ph y d el ays i ns ul i n a bs o rp t io n . D ia b e te s C a r e
1 9 8 4; 7 :4 7 9.
[ C r o ss R e f]
[ Me d l i n e L in k ]
7 3 . A D A . A me r ic an D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. S ta n da r ds o f me di ca l c a re fo r
p a t ie n ts wi t h d ia b et e s me l li t us . Di a be t es C ar e 2 00 4 ; 27 ( S up p l 1 ) : S1 5 .
7 4 . An o n. B r in gi n g me d ic i ne ho me : s el f - te s t ki t s m o ni t o r yo u r h e al th . C ons um e r Re p o rt s ,
O c t o be r 19 9 6.
7 5 . L e nh a rd MJ e t al . A c om p a ri so n b e t we e n a lt er n a ti ve a nd t ra de n am e g l uc os e t e st s t r ip s.
D i a b et es C a re 19 9 5; 1 8: 68 6 .
[ C r o ss R e f]
7 6 . Sk yl e r J S . Ta c ti cs for t yp e I d ia be t es . En d oc ri n ol Me t a b C li n No r t h Am 19 9 7; 2 6: 6 47 .
[ C r o ss R e f]
7 7 . G lu co wa t c h Bi og r a phe r : a n on i n vas i ve g lu co se mo n it o ri n g d e vic e . Me d L et t D r ug s Th e r
2 0 0 1; 4 3: 4 2.
7 8 . Pe t e rs AL , D a vid so n MB . E f f e c t of s t o ra g e o n a c ti o n o f N P H a nd r eg ula r in s ul in m i xt u r e s .
D i a b et es C a re 19 8 7; 1 0: 79 9 .
[ Me d l i n e L in k ]
7 9 . Tu nb r i dg e F K et al . D o u b le - bl i nd c r os s o ve r tr i a l o f i so ph a ne ( N P H ) - an d le n te - ba se d i ns u li n
r e g im en s . D i ab e te s C a r e 1 9 89 ; 12 : 11 5 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
8 0 . El i L il l y an d C om pa ny. H u m al o g P ac ka g e I nse r t . Ma y 2 0 0 2.
8 1 . A ven t is Ph a rm ac e ut ic a ls In c. La n tu s Pa ck age I ns e rt . Ma y 2 0 0 3.
8 2 . Pe r r ie l lo G et al . Th e e f f ec t o f a s ym p to m at ic n o ct u r na l h yp o gl yc em ia o n gl yc em ic c o nt r ol in
d i ab e te s m el li t us . N En gl J Me d 1 98 8 ;3 1 9: 1 23 3 .
8 3 . Sh a de D S , B u r g e , MR . B r i tl e Di a be t es : Pa t hog e n es is a n d Th e r a p y. I n : P o r t e D S , R S , e d.
E l l en b e rg & Ri fk i n 's D ia be t es Me l l i tu s , 5 th E d. S ta m fo r d , C T: A p p le t on & L a n ge , 1 9 97 : 78 9 .
8 4 . To r dj ma n K M e t al . Fa i lu r e o f n o ct u rn a l h yp ogl yc em i a t o c au se fa s ti ng h yp e r gl yc em i a in
p a t ie n ts wi t h i ns ul i n -d epe n d en t d i ab e te s me l li tu s. N E n gl J Me d 1 98 7 ;3 1 7: 1 5 52 .
8 5 . G e ri ch J E . L i ll y l ec tur e 1 98 8 . G l uc os e c ou n ter r e g ul a ti on a nd i t s im p act o n d ia b et es
m e ll i tu s. D ia b et es 19 8 8;3 7 : 16 0 8.
[ C r o s s R e f]
P . 5 0 -8 4
8 6 . Fa ne l li C G et al . Adm i ni st r a ti on o f n eu t r al pro t am i ne H ag e do r n i ns ul in a t b ed t im e ver s us
wi t h d i nn e r i n t yp e 1 di ab e t es m el l it us t o a vo id no c tu r n al h ypo gl yc em i a an d im p ro ve c o nt r o l. A
r a n do mi ze d , c on t r ol le d t ri a l . A n n I nt e r n Me d 2 0 02; 1 3 6: 5 04 .
8 7 . Ri d dl e MC e t al . Th e Tr e a t - t o - Ta rg e t Tr ia l : Ra n d om i zed ad di t io n o f gla r g in e o r hu ma n N P H
i n su li n to or a l t he r a p y o f t yp e 2 d ia be t ic pa t ie n ts . D i a be t es C ar e 20 03 ; 26 :3 0 8 0.
[ C r o ss R e f]
[ Me d l i n e L in k ]
8 8 . To r lo n e E et al . E ff ec t s o f t h e sh o r t - a ct i ng i ns u li n a na l og [L ys ( B 28 ) , P r o ( B 2 9) ] on
p o st p r an di a l b lo o d gl u cos e c on t r ol in I D D M. D i a be t es C a re 19 9 6; 1 9: 9 45 .
[ C r o ss R e f]
8 9 . Ca m pb el l PJ e t al . Pa t h og e ne si s o f t h e d a wn p h en om e no n i n p a ti en t s wi t h i ns ul i n d e p en de n t d ia b et es me lli t us . Ac ce l er a te d g l uc ose p r od uc t io n a nd im pa i r ed g lu co se ut i li za t io n
d u e t o n oc t u rn a l su r g e s in g r o wt h h o rm o ne s ec r e ti o n . N E ng l J Me d 1 98 5 ;3 1 2 :1 4 73 .
9 0 . Bo l li G B , Ge r ic h J E . Th e “ d a wn p he n om en on ” — a co mm on oc cu r r en ce i n bo t h n on - in su l in d e p en de n t a nd in su l in - de p e nd en t di ab e te s m el li tu s . N E n gl J Me d 1 98 4 ;31 0 : 74 6 .
9 1 . Zi nm an B e t al . I n su li n li sp r o i n C S I I : r es u lt s o f a d ou b le - bl i nd c r os sove r s t ud y. D ia b et es
1 9 9 7; 4 6: 4 40 .
[ C r o ss R e f]
9 2 . A D A . A me r ic an D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. H yp e rg l ycem ic C r is es in
D i a b et es . D ia be t es C a re 2 0 04 ; 27 : S 94 .
9 3 . A D A . A me r ic an D ia be t es A ss oc ia t io n Po si t ion S t at e me n t. Im pl ic a ti o ns o f t he D ia b et es
C o n t r ol an d Co mp l ic at i on s Tr i al . Di a be t es C ar e 2 0 0 3; 2 4( S u pp l 1 ) : S2 5 .
9 4 . Ag n e r T e t al . Re mi ss i on in I D D M: p r os p ec ti ve s tu d y of ba sa l C -p e pt id e an d i ns u li n d os e i n
2 6 8 c on se cu t i ve p a ti en t s. D i ab e te s Ca r e 1 9 87 ; 10: 1 6 4.
[ C r o ss R e f]
[ Me d l i n e L in k ]
9 5 . Be r e gs zas zi M e t a l. N o c t ur n al h ypo g l yc em i a i n c h il d re n a n d a do le sc en t s wi t h i ns ul in d e p en de n t d ia b et es me lli t us : pr e va le nc e a n d r is k f a ct o rs . J P ed ia t r 1 9 97 ;1 3 1 :2 7 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
9 6 . Sa n ti a go J V . N oc tu rn a l h yp o gl yc em ia in c h ild r e n wi t h d ia be t es : a n im p o rt a nt p ro bl em
r e vi s it e d. J P ed i at r 19 9 7; 1 3 1: 2 .
[ F u ll t e xt L in k ]
[ Me d l i n e L in k ]
9 7 . Be r ns t ei n R K. C lo u din g an d d e ac ti va t io n o f c le a r ( re g ul a r ) h um an in sul i n : as so ci a ti o n wi t h
s i li co ne oi l fr om di sp o sab l e s yr i ng es ? Di a be t es C a r e 19 8 7; 1 0: 7 86 .
9 8 . Be ns o n E A et al . Fl oc cu l at e d h um ul i n N in su li n . N En gl J Me d 1 9 87 ; 31 6 : 10 2 6.
[ Me d l i n e L in k ]
9 9 . St o r vic k W O, H en r y H J . E ff e ct of st o r ag e t emp e r a tu r e o n s ta bi l it y o f co mm e rc i al in su li n
p r e pa r a ti o ns . D i ab e te s 19 6 8 ;1 7 :4 9 9.
1 0 0 . Q i n g S hi Z e t a l . Me t a bo li c i mp li ca t io ns o f exe r c i s e a n d p h ysi ca l f i tne ss in ph ys i ol og y a nd
d i ab e te s . I n : P o r te D , J r , S h e r wi n R , e ds . El le n ber g ' s an d Ri fk i n 's D ia b et es Me l l i tu s , 5 th E d.
S t a mf o r d, C T: A p pl e to n & L a ng e , 1 99 7 :6 5 3.
1 0 1 . Z in ma n B e t a l . P h ys ic a l ac t i vi t y/e xe r c i se and d ia be t es m e ll i tu s. D ia be t es C a re
2 0 0 3; 2 6( S u pp l 1 ) : S7 3 .
[ Me d l i n e L in k ]
1 0 2 . Ma c D o n al d MJ . P ost e xe r c i se la t e -o ns e t h ypo g l yce mi a i n i ns ul i n -d epe n d en t d i ab e ti c
p a t ie n ts . Di ab e te s Ca r e 1 9 8 7; 1 0: 5 84 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 0 3 . K o i vis to V A , F el i g P. E f f ec ts of le g e xe r c i se o n in su li n a b so r pt i on in d i ab e ti c p a ti en t s. N
E n g l J Me d 19 7 8; 2 98 : 79 .
1 0 4 . K em me r FW e t a l. Me c h a n is m o f e xe r c i se - in d uc e d h yp og l yce mi a d ur i n g s ul f on yl u re a
t r e a tm en t . Di a be t es 1 9 87 ; 3 6: 1 17 8 .
[ C r o ss R e f]
1 0 5 . A D A . Me d i ca l Ma n ag e me n t o f I ns u li n - De p end e n t ( Typ e I ) D ia be t es Me l li t us , 3 r d Ed .
A l e xa n d r i a, V A : A me r ic an D i ab e te s A ss oc i at i on , 1 9 9 8.
1 0 6 . Tu r n h ei m K . Ba si c a s pe ct s o f i ns u li n p h ar ma c ok in e ti cs . I n : B r u ne t ti P , W ald ha us l W , ed s.
A d va n ce d Mo d e ls fo r th e Th e r a p y of I ns ul in - D e pen d e nt D ia b et es . N e w Yo r k : R a ven P r ess ,
1 9 8 7: 9 1.
1 0 7 . R u be ns t ei n A H , S pit z I . R ol e of th e k id n e y in i ns ul in me t ab ol is m a n d e xc r e t i on . D ia be t es
1 9 6 8; 1 7: 1 61 .
1 0 8 . R a bk in R et al . E ff ec t of r en al di se a se on ren a l u p ta ke an d e xc r e t i on o f i n su li n i n m an . N
E n g l J Me d 19 7 0; 2 82 : 182 .
1 0 9 . va n d e n B e r gh e G et a l. I nt e ns i ve i ns ul i n t her a p y i n t he c r i ti ca l l y i ll pa t i en ts . N En g l J
Me d 2 0 0 1 ;3 4 5: 1 35 9 .
[ C r o ss R e f]
1 1 0 . Ma l m b e rg K . P r os pe c ti ve r an d om is ed s t ud y o f in t en si ve in su l in t re a tm e nt on lo n g t e rm
s u r vi va l a ft e r a cu t e m yoc a r di al in f a rc ti o n i n p at i en t s wi t h d ia be t es m e ll i tus . D I G A MI ( D i a be t es
Me l l i t u s, In s ul in G l uc os e I n f us io n i n A c ut e Myo c ar d i al In f a rc t io n ) S t ud y G r o u p . B mj .
1 9 9 7; 3 14 : 15 12 .
[ F u ll t e xt L in k ]
1 1 1 . Mo n t o r i V M e t al . Hyp e r g l yce mi a i n a cu t el y il l pa t ie n ts . J A MA 2 0 02 ; 28 8 : 21 6 7.
[ F u ll t e xt L in k ]
[ C r o ss R e f]
1 1 2 . H i rs ch I B , Mc G i l l JB . R o le o f in s ul in in m a na g em e nt of su r gi ca l p a tie n ts wi t h di ab e te s
m e ll i tu s. D ia b et es C a re 1 9 9 0; 1 3: 9 80 .
[ C r o ss R e f]
1 1 3 . G a vi n L A . Pe r io p e ra t i ve m an a ge me n t o f t h e d i ab e ti c p at i en t . E n do c ri n ol Me t a b C li n No r t h
A m 19 9 2; 2 1: 4 57 .
1 1 4 . P a tt o n J S e t a l . I n ha l ed in su l in . Ad v D r u g De l i v R e v 1 9 99 ; 35 : 23 5 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 1 5 . R o yl e P e t a l. In h ale d in su li n i n d i ab e te s mel l it u s. C oc h ra n e D a ta b ase S ys t Re v
2 0 0 3: C D 0 03 8 90 .
1 1 6 . N a t ha n D M. I n ha le d i ns u li n f o r t yp e 2 di a be te s : s ol u ti on o r d is t ra c ti on ? A nn In t e rn Me d
2 0 0 1; 1 34 : 24 2 .
1 1 7 . C r ye r P E , G e r ic h J . H yp o g l yce mi a i n i ns ul i n - d e pe n de n t d ia b et es me ll i t us : i nt e r pl a y of
i n su li n e xc e s s a nd co mpr o m is ed gl uc os e re gu l at io n . In : Po r t e D , J r , e t a l , e ds . El l en b er g ' s a nd
R i f ki n ' s D i ab e te s Me l li t us , 6t h Ed . N e w Yo r k : Mc G r a w - H i l l , 20 0 3: 5 23 .
1 1 8 . P r am mi n g S et al . S ym p t om a ti c h yp og l yca em i a i n 4 11 t ype 1 d ia b et ic pa t ie n ts . Di a be t
Me d 1 9 9 1 ;8 : 21 7 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 1 9 . E n ni s E et al . D ia bet i c K e to a ci do si s . I n: P o rte D , J r , Sh e r wi n R , e ds . E l l en b e rg ' s a nd
R i f ki n ' s D i ab e te s Me l li t us , 5t h Ed . St a mf o rd , C T: A p p le t on & La ng e , 1 99 7 :8 2 7 .
1 2 0 . H i ll ie r TA e t a l . H yp o n a t re mi a : e va lu a ti ng t he co r r ec t io n f ac t o r f o r h yp e r gl yc e m ia . Am J
Me d 1 9 9 9 ;1 0 6: 3 99 .
[ C r o ss R e f]
1 2 1 . V i al lo n A e t a l . D o es bi ca r b on a te th e r ap y imp r o ve th e m an a ge me n t of s e ve re di ab e ti c
k e to ac i do si s? C r it C a re Me d 1 9 9 9 ;2 7 :2 6 90 .
1 2 2 . L eb o vi t z H E . a lp h a -G l u c os id as e i nh i bi t o rs . En d oc r in o l Me t a b C li n N ort h Am 1 99 7 ;2 6 :5 39 .
[ C r o ss R e f]
1 2 3 . Ma r t i n A E , Mo n t g om e r y P A . A ca r b os e: an al p ha - g lu co si d as e i nh ib i tor . A m J He a lt h S yst
P h a r m 1 99 6 ;5 3 :2 27 7 ;q u iz 2 3 3 6.
1 2 4 . Ye e H S , Fo n g N T. A r e vi e w o f th e s af e t y and e f fi ca c y o f ac ar b os e i n d i ab e te s me l li t us .
P h a r ma co t he r ap y 1 99 6 ;16 : 7 92 .
1 2 5 . C h ia ss on JL et al . Th e e f fi c ac y o f ac a rb o se i n t h e t r ea t me n t o f p a ti en t s wi t h n on - in su l in d e p en de n t d ia b et es me lli t us . A m ul t ic en t e r co n t ro l le d c li n ic al t ri al . A nn In t e r n Me d
1 9 9 4; 1 21 : 92 8 .
1 2 6 . C o ni f f RF e t a l. R edu c ti o n o f g l yco s yla t ed hem o gl o bi n a nd po s tp r an d ia l h ype r gl yc em ia b y
a c a rb os e i n p a ti en t s wi t h N I D D M. A p l a ce b o - co n t ro l le d d os e -c om p a ri so n st u d y. D ia b et es C a re
1 9 9 5; 1 8: 8 17 .
[ C r o ss R e f]
1 2 7 . B a ye r Co r p or a ti o n. P r e c os e P ac ka g e I ns e rt . Ma y 2 0 0 3 .
1 2 8 . P h a rm ac ia & Up j ohn C o mp an y. G l ys et P ac ka g e I ns e r t. Ju l y 20 0 3.
1 2 9 . Mi t r a k ou A e t al . L on g - t er m e f fe c ti ve ne ss of a n e w a lp h a - g lu co si d as e i n hi bi t o r ( B A Y
m 1 09 9 -m ig l it o l) in in su l in - t r ea t ed t yp e 2 d i ab e tes me ll i tu s . D i ab e t Me d 19 9 8 ;1 5 :6 5 7.
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 3 0 . K l ep se r TB , K el l y MW . Me t fo r mi n h yd r oc hl o ri d e : a n a nt i h ype r gl yc em ic ag e nt . Am J H e al t h
S ys t P h ar m 1 99 7 ;5 4 :8 9 3.
[ F u ll t e xt L in k ]
1 3 1 . W ild as in E M e t al . Me t f o r m i n, a p r om is in g or a l a n ti h yp e rg l yce mi c f o r t h e t r ea t me n t o f
n o ni n su li n -d e pe n de n t d ia b e te s me l li t us . P h a rm ac o th e r ap y 1 99 7 ;1 7 :6 2 .
1 3 2 . B e ll P M, H a d de n DR . Me t f o r m in . En d oc r in ol Me t a b C l in N o r th Am 199 7 ; 26 : 52 3 .
[ C r o ss R e f]
1 3 3 . B a il e y CJ , Tu r ne r RC . Me t f o r m in . N En gl J Me d 1 9 9 6 ;3 3 4 : 5 74 .
[ C r o ss R e f]
1 3 4 . K i rp ic h ni ko v D e t a l. Me t f o r m in : a n u p da t e. A n n In t e rn Me d 2 00 2 ;1 37 : 2 5.
1 3 5 . U K P D S 28 : a r an d om i ze d t r ia l o f e f fi c ac y o f e a r l y ad di t io n o f m e tf o rmi n in s u lf o n ylu r ea t r e a te d t yp e 2 di a be t es . U . K . P r os pe c ti ve D ia b ete s S tu d y G r ou p . Di ab e tes C a re 19 9 8; 2 1: 8 7.
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 3 6 . B r is t ol - Mye r s , S q uib b C om pa n y. G lu co p ha ge P ac ka g e I n s e r t. A p ri l 20 0 3 .
1 3 7 . S am b ol N C et al . Kid n e y fu n ct io n a n d a ge a re b ot h p r e di ct o rs of ph a rm ac o ki ne t ic s o f
m e t fo rm i n. J C l in P ha rma c ol 19 9 5; 3 5: 1 09 4 .
1 3 8 . G a n S C e t a l . B ig u an i de - as so ci a te d l a ct ic aci d os is . Ca s e r ep o r t a nd re vi e w o f t he
l i t er a tu r e . A r ch I nt e rn Me d 19 9 2; 1 52 : 23 33 .
[ C r o ss R e f]
1 3 9 . N o va r ti s Ph a rm ac eu t ic a ls Co r p o ra t io n . S t a rl i x P a c ka g e I ns e rt . N o vem b e r 2 00 2 .
1 4 0 . N o vo N o rd is k P h arm ac e ut ic a ls , I nc . P ra n din P ac ka g e I ns e r t. O ct o be r 2 00 2 .
1 4 1 . C u l y C R , J a r vis B. R e p a gl in i de : a r e vie w o f i t s t h er a pe u ti c u se i n t ype 2 d i ab e te s me l li t us .
D r u g s 2 00 1 ;6 1 :1 6 25 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
1 4 2 . H a t or p V. C li n ic a l ph a r ma co ki n et ic s a nd ph ar m ac o d yna mi cs o f r ep ag li n id e . Cl in
P h a r ma co ki ne t 20 02 ; 4 1:4 7 1 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
1 4 3 . H a ss la ch e r C. S af et y a n d e f fi ca c y of r ep a gl in i de in t yp e 2 d i ab e ti c pa t i en ts wi t h an d
wi t h o u t i mp a i re d r e na l f un c ti o n. D ia b et e s C a r e 2 00 3 ; 26 : 88 6 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 4 4 . N i em i M e t a l . E f f ect s of ge mf i b ro zi l , i t ra co na zo l e , a nd th e i r co mb i nat i o n o n t he
p h a rm ac ok i ne ti cs an d p ha r m ac od yn am ic s o f re pag l in i de : p o te n ti a ll y h a za rd o us in t e ra ct i on
b e t we e n g em f ib r o zil a nd r e p ag li n id e . D i ab e to lo g ia 2 00 3 ;4 6 :3 4 7.
1 4 5 . Z im me rm a n B R . S ulf o n yl u re as . En d oc r i n ol Me t a b C l in N o rt h Am 19 97; 2 6 :5 1 1.
[ C r o ss R e f]
1 4 6 . G r o op L C . S u lf o n ylu r e as in N I D D M. D i a be t es C a re 19 9 2; 1 5: 7 37 .
[ C r o ss R e f]
1 4 7 . Ma r c h e t ti P , N a va les i R . P h ar ma c ok in e ti c - ph a r ma co d yn am ic re la t io ns h ip s o f o r al
h yp o g l yc a em ic a g en ts . An u pd a te . Cl i n P h a rm ac ok i ne t 1 9 89 ; 16 : 10 0 .
[ C r o ss R e f]
1 4 8 . G r o op L C e t a l . E f fe c t o f s ul p ho n ylu r e a o n g l uc os e -s t im ul a te d i ns ul in s e c re t io n i n h e al t h y
a n d n o n - i ns ul in d ep en d en t di a be t ic s ub j ec ts : a do s e -r e sp on se st u d y. Ac ta D i ab e to l
1 9 9 1; 2 8: 1 62 .
[ C r o ss R e f]
1 4 9 . W ahl in - B ol l E e t a l. I m pa i re d e f fe c t o f s ul f on yl u r ea f ol lo wi n g in c re ase d do sa g e. E u r J Cl in
P h a r ma co l 1 98 2 ;2 2 :2 1 .
[ C r o ss R e f]
1 5 0 . S t en ma n S e t a l . W h a t i s t h e b en e fi t o f i nc re a si n g t he s u lf o n ylu r ea d o se ? An n I n te r n Me d
1 9 9 3; 1 18 : 16 9 .
1 5 1 . W ahl in - B ol l E e t a l. B i o a vai la b il i t y, p ha r ma co k in e ti cs a n d e f fe ct s o f g l ip i zi de in t ype 2
d i ab e ti cs . Cl i n P h a rm ac ok i ne t 1 9 82 ; 7: 3 63 .
[ C r o ss R e f]
1 5 2 . Ja b e r L A e t a l . Co mp a r is on o f p ha r ma co ki net i cs an d p ha r ma co d yn ami cs o f sh o r t - a nd
l o ng - t e rm g l yb u ri de t he ra p y i n N I D D M. D i a b e te s C a r e 19 9 4; 1 7: 1 30 0 .
[ C r o ss R e f]
1 5 3 . F el dm a n J M. G l yb ur i d e: a s ec on d - ge ne r a ti on su l fo n yl u re a h yp o gl yc em ic ag e nt . H is to r y,
c h em is t r y, m et a bo l ism , ph a r ma co ki n et ic s, cl in ic a l u se an d a d ve rs e e f f ec ts. P h a rm ac ot h e ra p y
1 9 8 5; 5 :4 3 .
[ Me d l i n e L in k ]
1 5 4 . F ab e r O K e t a l . A c ut e ac t io ns of su l fo n ylu r ea d r ug s d u ri ng lo n g - t e rm t r e at me n t o f N I D D M.
D i a b et es C a re 19 9 0; 1 3 (S u p pl 3 ): 2 6.
[ Me d l i n e L in k ]
1 5 5 . S o nn e nb e rg G E et a l . Sh o r t - t e rm c om p a ri son o f o nc e - ve r su s t wi c e -d a il y a dm in is t r a ti on of
g l im ep i r id e i n p a ti en t s wi t h no n - in su li n - de pe n de n t d i ab e te s me l li t us . A n n Ph a r ma co t he r
1 9 9 7; 3 1: 6 71 .
1 5 6 . R o se nk r an z B . P ha rm ac o ki ne t ic b a si s f o r t he s a fe t y o f gl im e pi r id e i n r i sk g ro up s o f
N I D D M p a t i e n ts . Ho r m Me t a b R e s 1 99 6 ;2 8 :4 34 .
[ C r o ss R e f]
1 5 7 . D r a eg e r KE e t a l. Lo n g - te rm t r ea tm e nt of t yp e 2 d ia b et ic pa t ie n ts wit h t he ne w o r a l
a n t id ia b et ic ag e n t gl im ep i r id e ( Am ar yl ) : a d ou bl e - b l in d c om pa r is o n wi t h gli b en cl a mi de . H or m
Me t a b R e s 1 9 96 ; 28 : 41 9 .
[ C r o ss R e f]
1 5 8 . K o da - K im bl e MA , R o t b la t t M. D i a b e te s m el lit u s . I n: Yo u n g L , Ko da - Ki m bl e MA , e ds .
A p p li e d Th e r a pe u ti cs . Th e C li ni c al Us e o f D r ug s, 4 t h E d . Va nc o u ver , W A: A p p li ed
Th e r a p eu t ic s, 19 8 8: 1 66 3.
1 5 9 . E a rl e y L E . C h lo r p rop a mi d e a nt id i u re si s. N En g l J Me d 19 7 1; 2 84 : 10 3 .
1 6 0 . S p ie ge lm a n B M. P P A R - g a mm a: ad i po ge n ic re g ul a to r an d th ia zo l id in ed i on e re ce p to r .
D i a b et es 19 9 8; 4 7: 5 07 .
[ C r o ss R e f]
1 6 1 . Mu d a l ia r S , He n r y R R . N e w o r a l t h e ra pi e s fo r t yp e 2 d i ab e te s m el li tu s : Th e g li ta zo n es o r
i n su li n s en si t i ze rs . An n u R e v Me d 2 0 0 1; 5 2: 2 39 .
[ C r o ss R e f]
1 6 2 . Ma l i n o ws ki J M, B o le s ta S . Ro si g li t a zon e i n t h e tr e at me n t o f t ype 2 di a be t es m e ll i tu s: a
c r i ti ca l re vi e w. C l in Th e r 2 0 00 ; 22 : 11 5 1; d isc us si on 1 14 9 .
P . 5 0 -8 5
1 6 3 . I n zuc ch i S E. O r al an t i h ype r gl yc em ic th e r ap y f o r t ype 2 d ia be t es : s ci en t i fi c r e vi e w. J A MA
2 0 0 2; 2 87 : 36 0 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
1 6 4 . S a to h N e t a l . A n ti at h e r og en ic e ff ec t of pi o gli t a zo ne in t ype 2 d ia b et ic pa t ie n ts
i r r es p ec ti ve o f t he r es pon s i ven es s t o i ts an t id i abe t ic e ff ec t . Di a be t es Ca re 2 00 3 ;2 6 :2 4 93 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 6 5 . G l a xo S m i th K li n e. Ava n d i a P ac ka g e I ns e rt . Ma r c h 2 0 03 .
1 6 6 . H a ne f el d M. P h a rma c ok in e ti cs an d c li ni ca l e f f ic ac y o f p io g li t a zon e . I n t J C li n P ra ct S up p l
2 0 0 1: 1 9.
1 6 7 . Ta k ed a Ph a rm ac e uti c al s A me r ic a , I nc . a n d El i Li ll y a nd C om pa n y. Ac to s Pa ck ag e In se r t .
J u l y 2 0 02 .
1 6 8 . S a lt i el A R , O l e fsk y J M. Th i a zo l i di n ed io n es in t he t re a tm en t of in su l in r es is t an ce an d t ype
I I di a be t es . Di a be t es 1 99 6 ; 45 : 16 6 1.
[ C r o ss R e f]
1 6 9 . A l - Sa lm a n J e t a l . H e p a to ce l lu la r in ju r y i n a p at i en t re ce i vi ng ro si g li t a zo ne . A c as e r e po r t .
A n n In t e rn Me d 2 00 0 ;1 32 : 1 21 .
1 7 0 . F o rm an L M e t al . He p a ti c f ai l ur e i n a pa t ie nt t ak i ng ro si g li t a zon e . A nn I n te r n Me d
2 0 0 0; 1 32 : 11 8 .
1 7 1 . L eb o vi t z H E e t a l . Eva l u a ti on o f l i ve r f un ct i on i n t yp e 2 di ab e ti c p a t i en t s d u ri n g cl i ni ca l
t r i al s : e vi de nc e t h at r os ig l i ta zo ne d oe s n ot ca us e h e pa t ic d ys f un ct i on . Di ab e t es C ar e
2 0 0 2; 2 5: 8 15 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 7 2 . H e n r y R R . Thi a zo lid i ne d io n es . E n do c ri n ol Me t a b C l i n N o r th A m 1 99 7 ; 26 : 55 3 .
[ C r o ss R e f]
1 7 3 . N i em e ye r N V , J a nne y L M. Th i a zo l i di n ed io n e - i n du ce d e d em a. P ha r mac o th e r ap y.
2 0 0 2; 2 2: 9 24 .
[ C r o ss R e f]
1 7 4 . K e ll y I E e t al . Ef f ect s of a t hi a zo li di n ed i on e c om p ou n d o n b od y f a t an d fa t di st r ib u ti o n o f
p a t ie n ts wi t h t yp e 2 di a be t es . D ia b et es C a re 19 99 ; 2 2: 2 88 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 7 5 . W inkl e r K e t a l. P iog l i ta zo ne r ed uc e s a th e rog e ni c d e ns e L D L p a rt ic l es in no n di a be ti c
p a t ie n ts wi t h a r t er i al h ype r t e ns io n : a d o ub le - b li nd, p la ce b o -c on t r ol le d s t udy. D i a be t e s C a re
2 0 0 3; 2 6: 2 58 8 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 7 6 . Ti g h t b lo o d p r ess u re co n t ro l a n d r is k o f m acr o va sc u la r an d m ic ro va sc u la r c om p li ca t io ns in
t yp e 2 d ia b et es : U K P D S 3 8 . U K Pr os p ec ti ve D i abe t es S t ud y G r o up . B r Me d J 1 99 8 ;3 1 7: 7 03 .
1 7 7 . E f fi ca c y of a te n ol ol a n d c ap t op r il in r ed uc i ng r i sk o f m ac r o vas cu l a r an d m ic r o vas cu l a r
c om p li ca t io ns in t ype 2 di a be t es : U K P D S 3 9 . U K P r o s pe ct i ve Di a be t es S tu d y G r o up . B r Me d J
1 9 9 8; 3 17 : 71 3 .
1 7 8 . C o l we l l J A. D C C T f in d in g s. A pp li ca b il i t y a n d i mp l ic at i on s f o r N I D D M. D i a be t es R es
1 9 9 4: 2 77 .
1 7 9 . C o l we l l J A. S ho u ld we u s e i n t en si ve in su li n t h e r ap y a ft e r o r a l a ge n t fa i lu r e i n t yp e II
d i ab e te s ? D i ab e te s C a r e 1 9 96 ; 19 : 89 6 .
1 8 0 . H e n r y R R , Ge n ut h S . F o ru m On e : Cu r r en t re c omm e nd a ti o ns a b ou t in t e ns if ic a ti o n o f
m e ta b ol ic c o nt r o l i n n on -i n su li n - de pe n de n t d ia b ete s m el l it us . An n In t e rn Me d 19 9 6; 1 24 : 17 5 .
1 8 1 . F aa s A e t a l. Th e eff i ca c y of se l f - mo n it o r in g o f bl o od gl uc os e i n N I D DM s u b j ec t s. A
c r i te r ia - b as ed li t er a tu r e r e vi e w. D i a be t es C ar e 19 9 7 ;2 0 :1 4 82 .
[ C r o ss R e f]
1 8 2 . A vi g no n A e t a l. N on f as t in g p l asm a g l uc os e i s a be t t er ma r ke r o f di ab e t ic c on t r ol th a n
f a s ti ng pl as ma gl uc o se in t yp e 2 di ab e te s . D i ab et e s Ca r e 1 99 7 ;2 0 :1 8 22 .
[ C r o ss R e f]
1 8 3 . L eb o vi t z H E . S t ep wi s e a nd c om b in a ti o n d rug t he r a p y f o r th e t r ea t men t o f N I D D M.
D i a b et es C a re 19 9 4; 1 7: 15 4 2 .
[ Me d l i n e L in k ]
1 8 4 . A me r ic a n D i ab e te s A s so ci a ti o n ( A D A ) . Th e p h a rm ac ol o gi ca l t r e at men t o f h yp er g l yce mi a i n
N I D D M. D i a b e t es C a re 19 9 6 ;1 9 ( Su p pl ) : 54 .
1 8 5 . N a t ha n D M. C l in ic a l p r ac t ic e. I ni t ia l m an ag em e nt o f g l yc em i a i n t yp e 2 di a be t es m el l it us .
N E n g l J Me d 20 0 2; 3 47 :1 3 4 2.
[ C r o ss R e f]
1 8 6 . C h a rp e nt i er G . O r al c om bi n at i on th e r ap y f o r t yp e 2 d ia b et es . D ia b et es Me t a b R es R e v
2 0 0 2; 1 8( S u pp l 3 ) : S7 0 .
[ C r o ss R e f]
1 8 7 . G a vi n L A et al . Tr og l i ta zo ne a dd - on th e r ap y t o a co mb i na t io n o f s ul fo n yl u re as pl us
m e t fo rm i n ac h ie ve d a n d s us t ai n ed ef f ec t i ve d ia be t es co n t ro l. E nd o cr P r ac t 20 00 ; 6 :3 05 .
[ Me d l i n e L in k ]
1 8 8 . B e ll D S , O va l l e F . Lo n g - te rm e ff ic ac y o f t r i ple o r al th e ra p y f o r t yp e 2 d i ab e te s m el li t us .
E n d oc r P ra c t 2 00 2 ;8 : 27 1.
[ Me d l i n e L in k ]
1 8 9 . K a ye TB . Tr i pl e o r al a nt i di ab e ti c t h er a p y. J D i a b et es C om pl ic a ti o ns 1 9 9 8; 1 2: 3 11 .
1 9 0 . S ch wa r t z S e t a l . I ns u li n 7 0 /3 0 m i x p l us m e tfo r m in ve rs us t ri p le or a l th e r ap y i n t h e
t r e a tm en t o f t ype 2 d ia be t es a ft e r f a il u re of t wo o r a l d r ug s: e ff ic ac y, sa f et y, a n d co s t a na l ysi s.
D i a b et es C a re 20 0 3; 2 6: 22 3 8 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 9 1 . W rig h t A et al . S ul fo n yl u re a i n ad e qu ac y: e ffi c ac y o f a dd i ti on o f i ns uli n o ve r 6 yea r s i n
p a t ie n ts wi t h t yp e 2 di a be t es in t he U . K. P r os pe ct i ve D ia b et e s S t ud y ( U KP D S 5 7 ) . D i ab e te s
C a r e 20 0 2; 2 5: 3 30 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
1 9 2 . Tu r n e r R e t a l . U n ite d K in gd om P r os pe c ti ve D i a b et es S tu d y 1 7: a 9 - ye a r up da t e o f a
r a n do mi ze d , c on t r ol le d t ri a l o n t h e e ff e ct of im p rove d me t ab o li c c on t ro l o n c om pl ic a ti o ns i n
n o n -i ns u li n -d e pe n de n t d ia b e te s me l li t us . A n n I n ter n Me d 1 9 96 ; 12 4 :1 3 6 – 145 .
1 9 3 . E f fe c t o f i n te ns i ve b l oo d - gl uc os e c on t r ol wi th me t f or mi n o n c om pl i cat i o ns i n o ve r we i g h t
p a t ie n ts wi t h t yp e 2 di a be t es ( U K P D S 3 4 ) . U K P ro s pe ct i ve D ia be t es S tu dy ( U K P D S ) G r o u p .
L a nc e t 1 99 8 ;3 5 2: 8 54 .
1 9 4 . Me l a n d er A et al . Su l f on yl u re as . W h y, wh i c h, a nd ho w? D i a be t es C a re 1 99 0 ;1 3 ( Su p pl
3 ) : 1 8.
1 9 5 . K r a dj an W A e t a l . Ph a r ma co ki n et ic s a nd ph ar m ac o d yna mi cs o f gl ip i zid e af t e r o nc e -d ai l y
a n d d i vid e d d os es . Ph a rm ac o th e r ap y 1 99 5 ;1 5 :4 65 .
1 9 6 . L ea h y JL . Na t u ra l hi s to r y o f b e ta - ce ll d ysf u nc t io n i n N I D D M. D i a be t es C a re 19 9 0; 1 3: 9 92 .
[ C r o ss R e f]
1 9 7 . D e F ro n zo R A , G o o dm a n A M. E f f i ca c y of m e tf o r mi n i n p a ti en t s wi t h no n - in su l in - de p en d en t
d i ab e te s m el li t us . Th e Mu l t ic en t e r Me t f o r mi n St ud y G r o u p . N E ng l J Me d 1 9 9 5; 3 33 : 54 1 .
[ C r o ss R e f]
1 9 8 . F on se c a V et al . E ffe c t o f m et f o rm in an d ro s ig l i ta zo ne co mb i na t io n t he r a p y in pa t ie n ts
wi t h t yp e 2 d ia be t es m e lli t us : a r an d om i zed co n tro l le d tr i al . J A MA 2 0 0 0 ;28 3 : 16 9 5 - 1 70 2 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
1 9 9 . B e ll D , Ma yo M. O u t c om e o f m e tf o rm in - f ac il it a t ed r ei ni t ia t io n o f or a l d i ab e ti c t h e ra p y in
i n su li n - t re a te d p a ti e nt s wi t h n o n -i ns ul i n -d ep e nde n t d i ab e te s me l li t us . E nd o c ri ne P r ac ti ce
1 9 9 7: 7 3.
2 0 0 . W hit e J . C o mb in a tio n o ra l a ge n t /i ns ul i n t her a p y i n p at i e n ts wi t h t ype I I d ia b e te s me l li tu s .
C l i n Di a be t es 1 9 97 : 10 2 .
2 0 1 . Jo h ns on JL et al . Ef f i ca c y o f i n su li n a n d su lf o n yl u re a c om bi na t io n the r a p y in t ype I I
d i ab e te s . A me t a - a na l ysis o f t he r an d omi ze d pl ace b o -c on t r ol l ed t ri al s . A r ch I n te r n Me d
1 9 9 6; 1 56 : 25 9 .
[ C r o ss R e f]
2 0 2 . Yk i - Ja r vi ne n H . C om b in a ti on t he r ap i es wi t h i ns u li n i n t yp e 2 di a be t es . D ia be t es C a re
2 0 0 1; 2 4: 7 58 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 0 3 . Yk i - Ja r vi ne n H . C om b in a ti on t he r ap y wi t h in s ul in an d or a l a ge n ts : op t im i zi ng gl yc em ic
c o nt r o l i n p at i en ts wi t h typ e 2 d i ab e te s m el li t us . D i a b et es Me t a b R es R e v 2 0 02 ; 18 ( S up p l
3 ) : S 77 .
[ C r o ss R e f]
2 0 4 . Yk i - Ja r vi ne n H e t a l. C o mp a ri so n o f in su li n re g im e ns i n p a ti e nt s wi t h n o n -i ns u li n d e p en de n t d ia b et es me lli t us . N En g l J Me d 1 9 92 ;3 2 7 :1 4 26 .
2 0 5 . F r it sc he A et al . G lim e pi r id e c om bi n ed wi t h m o r ni ng in su l in gl a rg i ne , b e dt im e n e ut r a l
p r o t am in e h ag e do r n i ns ul i n , o r b ed t im e i ns ul i n g la r g in e i n p a ti e nt s wi t h t yp e 2 d ia b et es . A
r a n do mi ze d , c on t r ol le d t ri a l . A n n I nt e r n Me d 2 0 03; 1 3 8: 9 52 .
2 0 6 . D eW it t D E, H i rs ch IB . O u t pa t ie n t i ns ul i n t her a p y i n t yp e 1 an d t yp e 2 d i ab e te s me l li t us :
s ci e nt i fi c r e vi e w. J A MA 2 0 0 3; 2 89 : 22 54 .
[ F u ll t e xt L in k ]
2 0 7 . G i u gl ia n o D e t a l. Me t f o rm in fo r ob es e , i ns ul in - t r ea t ed di a be t ic p a ti e nt s : i mp r o vem e nt in
g l yc ae mi c c on t ro l a n d r ed u ct i on of me t ab ol ic r is k f a ct o rs . Eu r J C li n Ph a rm ac o l 1 99 3 ;4 4 :1 0 7.
[ C r o ss R e f]
2 0 8 . Mc N u l t y e t a l . C omp a r is on o f me t fo r mi n a n d s ul f on yl u r ea (g l ic a zid e ) i n c om b in a ti on wi t h
d a il y N P H i ns ul i n in t yp e 2 di a be t ic p a ti e nt s i na de q u at el y c on t r ol le d o n m a xi m a l o ra l t h er a p y
[ A b s tr ac t #0 62 2 ] . D i ab e te s 1 9 97 : 16 1 A .
2 0 9 . Yk i - Ja r vi ne n H e t a l. C o mp a ri so n o f be d ti me i ns u li n r e gi me ns in pa t ie n ts wi t h t ype 2
d i ab e te s m el li t us . A r a ndo m i zed , c on t r ol l ed t ri al . A n n In t e rn Me d 1 99 9 ;1 30 : 3 89 .
2 1 0 . R o se ns t ock J e t a l. E f f ic a c y a n d sa f e t y o f p io g li t a zon e i n t ype 2 d ia be t es : a r an d om is ed ,
p l ac e bo -c o nt r o ll ed st u d y i n p a ti e nt s r ec e i vin g s t ab l e i ns ul i n t he r a p y. I n t J C l i n Pr a ct
2 0 0 2; 5 6: 2 51 .
2 1 1 . R i dd l e MC . Ta c t i cs f o r t ype I I d ia b et es . E ndo c r in ol Me t a b C li n No r t h A m 19 9 7; 2 6: 6 59 .
[ C r o ss R e f]
2 1 2 . G e n ut h S. Ma n a g em e nt o f t he ad u lt on se t d i ab e ti c wi t h su l fo n yl u rea d r ug fa il u r e.
E n d oc r in o l Me t a b C li n No r t h Am 1 9 92 ; 21 : 35 1 .
2 1 3 . D eW it t D E, D u gd al e D C . U s in g n e w i ns ul i n st r a t eg i es i n t h e o ut p at i en t t re a tm en t of
d i ab e te s : cl i ni ca l a p pl ic at i o ns . J A MA 2 0 0 3; 2 89 : 226 5 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 1 4 . H a ywa r d R A e t a l. S t a r t in g i ns ul i n t he r a p y in p at i en ts wi t h t ype 2 d ia b e te s: e ff ec t i ven es s ,
c om p li ca t io ns , a n d r es o ur c e u t il i za ti on . J A MA 1 9 97 ; 2 78 : 16 6 3.
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 1 5 . C o l we l l J A. C o nt r ol li n g t yp e 2 di a be t es : a r e t h e b e ne f it s wo r t h t he cos t s? J A MA
1 9 9 7; 2 78 : 17 00 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 1 6 . A n de r so n J H , J r , e t a l . Me a l t im e tr e a tm en t wi t h i ns u li n a n al og im p rove s po s tp r an d ia l
h yp e r gl yc em i a a nd h ypog l yc em ia in pa t ie n ts wi t h n o n -i ns ul i n - d ep e nd e nt di a be t es m e ll i tu s.
Mu l t i c e nt e r I ns u li n L is p ro S t ud y G r o u p. A rc h I n t er n Me d 1 9 97 ; 15 7 :1 2 49 .
[ C r o ss R e f]
2 1 7 . D e sp r es J P et al . Hyp e r i ns ul i ne mi a a s a n i nd e p en de n t r is k f ac t o r f o r i sc he mi c h ea r t
d i se as e . N E n gl J Me d 19 9 6 ;3 3 4: 9 52 .
[ C r o ss R e f]
2 1 8 . W ing ar d D L e t a l. Is i ns u li n r e al l y a h ea r t d ise a se r isk f ac to r . Di a be t es C a re
1 9 9 5; 1 8: 1 29 9 .
2 1 9 . B o r de rs L M e t al . Tr a d it i on a l i ns ul in - us e p r ac t ic es an d t h e i nc id e nc e o f ba c te r ia l
c o nt am i na t io n a n d i nf ec ti o n . D i ab e te s C a r e 1 98 4 ;7 : 1 21 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 2 0 . Mi s b i n R I et al . L a ct i c a ci do si s i n p a ti en t s wi t h d i ab e te s t r ea t ed wi t h m e t fo rm i n. N E ng l J
Me d 1 9 9 8 ;3 3 8: 2 65 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 2 1 . C u si K , D e F ro n zo R. Me t f o r m in : a r e vie w o f it s m e ta b ol ic ef f ec ts . Di ab e t es R e vie w
1 9 9 8; 6 :8 9 .
2 2 2 . U n i ve rs it y G r o u p D ia b e te s P r o gr am : a s tu d y o f th e e f fe c ts o f h ypo gl yc em ic ag e nt s o n
va s c ul a r co mp l ic at i on s in p at i en ts wi t h ad ul t - on se t di a be t es I. D es ig n , me t h od s, an d b a se li n e
r e s ul ts . D ia be t es 19 70 : 74 7 .
2 2 3 . K i lo C e t al . Th e A ch i ll es he e l o f t h e U n i ve rsi t y G r o u p D i ab e te s P r o gra m . J A MA
1 9 8 0; 2 43 : 45 0 .
[ C r o ss R e f]
2 2 4 . S a r to r G et al . Te n -ye a r f ol l o w - u p o f s ub j ec ts wi t h im pa i re d g l uc os e to l e ra nc e : p r e ven t io n
o f di a be t es b y t o lb u ta mid e an d d i et r eg ul a ti o n. Di a be t es 19 8 0; 2 9: 4 1.
[ C r o ss R e f]
2 2 5 . Mi s b i n R I . Ph e nf o rm i n -a ss oc ia t ed la ct ic ac id o si s: pa t ho g en es is an d t r e a tm en t . An n I n te r n
Me d 1 9 7 7 ;8 7 :5 9 1.
2 2 6 . P h en f o rm in : re mo va l f ro m t he ge n e ra l m ar ke t . F D A D r u g B u ll 19 77 ;A u g : 19 .
2 2 7 . S t an g M e t al . In ci de n ce of la c ti c ac i do si s i n m e tf o rm in us e rs . Di a be te s C ar e
1 9 9 9; 2 2: 9 25 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 2 8 . E ms li e - Sm i th A M e t a l . C o n tr a in d ic at i on s t o m e t fo rm i n t he r a p y i n p a tie n ts wi t h Typ e 2
d i ab e te s —a po p ul a ti o n - ba s ed s t u d y o f a d he r e nc e t o pr es c ri b in g g ui d el i nes . D ia be t Me d
2 0 0 1; 1 8: 4 83 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 2 9 . C a la b re s e A T e t al . E va l u at i on of p re sc r ib ing p r ac ti ce s : r is k o f l ac ti c a ci d os is wi t h
m e t fo rm i n t he r a p y. A r ch I n t e rn Me d 2 00 2 ;1 6 2: 4 34.
[ C r o s s R e f]
2 3 0 . H o r le n C e t a l . F r equ e nc y o f i na p p ro p ri a te me t f o rm in p re sc r ip ti o ns . JA MA 2 0 0 2 ; 2 87 : 25 0 4.
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 3 1 . Ma s o u di F A e t a l . Me t f o r m i n a nd th i a zol i din e di o ne us e i n Me d ic a re p a ti e nt s wi t h h ea r t
f a i lu r e. J A MA 2 0 03 ; 29 0 :8 1 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 3 2 . S we d k o P J e t a l . Se r u m c re a ti ni n e is an in ad e q ua t e sc r ee n in g t es t fo r r en a l f ai l ur e i n
e l de r l y pa t ie n ts . A rc h I nte r n Me d 2 00 3 ;1 6 3: 3 56 .
[ C r o ss R e f]
2 3 3 . S e lt ze r H S . D ru g -i nd u ce d h yp o gl yc em ia . A re vi e w o f 1 41 8 c as es . End o c ri no l Me t a b Cl in
N o r t h Am 1 9 89 ; 18 : 16 3 .
2 3 4 . P e a rs on J G e t a l. Ph a r ma co ki n et ic di sp os i tio n of 14 C - g l ybu r id e i n pa t i en ts wi t h va r yi ng
r e n al f un ct i on . Cl i n P h arm ac o l Th e r 19 8 6; 3 9: 3 18 .
2 3 5 . G u l at i P e t a l. A dou b le - b li nd t ri a l o f t ol b u tam i de in c i r rh os is o f t he live r . A m J Di g Di s
1 9 6 7: 4 2.
2 3 6 . U e da H et al . D is app e a ra nc e ra t e o f t h e t ol bu t am i de in no r ma l s ub jec t s a nd in di ab e te s
m e ll i tu s, li ve r c i r rh os is , a n d re na l d is e as e. D i ab et e s 1 96 3 :4 1 4.
2 3 7 . G a mb e r t S R . A t ypi ca l pr e se n ta t io n o f d i ab e te s m el l it us in th e el de r l y. C l in G e r ia t r Me d
1 9 9 0; 6 :7 2 1.
[ Me d l i n e L in k ]
2 3 8 . Mo r l e y J E , Pe r r y HM, 3 r d . Th e ma n ag em e nt o f di ab e te s m el li t us i n ol d e r i nd i vi du al s .
D r u g s 1 99 1 ;4 1 :5 4 8.
[ C r o ss R e f]
2 3 9 . C a r li sl e B. D ia b et es i n t h e e ld e rl y: f ac t or s t o c on si d e r. P ha r m Ti m es 1 9 9 2: 1 30 .
P . 5 0 -8 6
2 4 0 . Ma t z R . H yp e r p sm ol a r H yp e ro sm ol a r S yn d r om e . I n : P o r te D , J r , e t a l, e ds . El le n be r g ' s
a n d Ri fk i n 's D ia b et es Me l l it u s, 6t h Ed . N e w Yo r k : Mc G r a w - H i l l , 20 03 : 58 7 .
2 4 1 . S i l ver A J, Mo r l e y JE . R o le o f t he op i oi d s yst e m i n t h e h yp od ip si a a ss oc i at e d wi t h a gi ng . J
A m G e ri a t r S oc 1 99 2 ;4 0 :5 5 6 .
2 4 2 . Mo r l e y J E e t al . Di ab e t es m el l it us in el d er l y p a t ie n ts . I s i t d i ff e re n t? A m J Me d
1 9 8 7; 8 3: 5 33 .
2 4 3 . B r o wn A F e t al . G uid e li n es fo r i m pr o vi ng th e c a re of t he ol de r pe r so n wi t h d ia b et es
m e ll i tu s. J A m G e r ia t r So c 2 0 03 ; 51 : S 26 5 .
[ F u ll t e xt L in k ]
2 4 4 . Mo k d a d A H e t a l. Pr e va l en ce o f o be si t y, di ab e t es , a nd ob e si t y - r el a ted h ea l th ri sk fa c t o r s,
2 0 0 1. J A MA 2 0 0 3 ;2 8 9: 7 6.
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 4 5 . H o gi k yan R , H al te r J . A gi ng an d Di a be t es . In : P o rt e D S , R S , Ba r o n A , e ds . El le n be r g a nd
R i f ki n ' s D i ab e te s Me l li t us , 6t h Ed . N e w Yo r k : Mc G r a w H i l l , 20 03 : 4 15 .
2 4 6 . G r e en b la t t DJ . Re du c ed s e r um a l bu mi n c onc e nt r a ti o n i n t he el d er l y: a r ep o r t f r om th e
B o s to n Co l la b or a ti ve D ru g S ur ve i ll a nc e P r og r am. J Am G e ri a tr S oc 19 79 ;2 7 : 20 .
2 4 7 . S h o rr R I e t al . I n di vi d ua l s ul f on yl u r ea s a nd se r i ou s h yp og l yc em ia i n ol d e r p eo p le . J Am
G e r i a t r S oc 19 9 6; 4 4: 7 51.
[ F u ll t e xt L in k ]
2 4 8 . F aj a ns S. C l ass i fi cat i o n a nd di ag n os is of di ab e t es . I n : P o r te D , J r , Sh e r wi n R , e ds .
E l l en b e rg ' s a nd R i fk in ' s D i a b et es Me l l i tu s, 5 th Ed . S ta m fo r d , C T: A p pl e ton & La n ge , 1 9 97 : 35 7 .
2 4 9 . F aj a ns S S e t a l . Mo l e cu la r me ch an is ms an d c l in ic al pa t ho p h ysi ol o g y o f ma t ur i t y - on se t
d i ab e te s o f th e you n g. N E n g l J Me d 2 0 01 ; 34 5 :9 71 .
[ C r o ss R e f]
2 5 0 . A r a u z - Pa ch e co C e t a l . H yp e r t en si on ma na ge m en t i n a d ul ts wi t h di abe t es . D ia b et es C a re
2 0 0 4; 2 7( S u pp l 1 ) : S6 5 .
2 5 1 . C o op e r ME , J oh ns to n C I . O p t im i zin g t r e at me n t o f h ype r t en si on in pat i e nt s wi t h d ia be t es .
J A MA 2 0 0 0 ;2 8 3: 3 17 7 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 5 2 . R e mu zzi G e t a l. C li n ic al p ra c ti ce . Ne p h ro pat h y i n p a ti en t s wi t h t yp e 2 d ia be t es . N En gl J
Me d 2 0 0 2 ;3 4 6: 1 14 5 .
[ C r o ss R e f]
2 5 3 . A D A P os it i on S ta t em e nt . N ep h ro p at h y in D ia b e te s. D i ab e te s C a r e 20 0 4 ;2 7 ( Su p pl 1 ): S 79 .
2 5 4 . R i t z E , O r t h S R . N ep h r op a th y i n p a ti en t s wi t h t yp e 2 di ab e te s m el li t us . N En g l J Me d
1 9 9 9; 3 41 : 11 27 .
[ C r o ss R e f]
2 5 5 . L te i f A A e t a l. D ia be t es an d h e a rt di se as e an e vi de nc e -d r i ve n g ui d e t o r isk f ac to r s
m a na g em en t i n d i ab e te s. C a r di o l R e v 20 0 3; 1 1: 2 62 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 5 6 . Yo u n g L , Ch yu n D . H e a r t Di se a se i n Pa t ie n ts wi t h D ia b et es . In : Po r te D S , R S , B a r on A ,
e d s. E ll e nb e rg an d Ri f kin ' s D ia b et es Me l l i tu s , 6 th E d . N e w Yo r k : Mc G r a w - H i l l, 20 0 3 :8 23 .
2 5 7 . H a f fn e r S M. D ys l i p id e mi a Ma n a ge me n t i n a du l ts wi t h di ab e te s . D i ab et e s Ca r e
2 0 0 4; 2 7( S u pp l 1 : S 68 .
2 5 8 . C o ns en su s d e ve lo pm e nt co n fe r en ce on t he d i ag n os is of c o r on a r y hea r t di se as e i n p e op le
wi t h d i a b e te s: 10 - 1 1 F ebr u a r y 19 9 8 , Mi a m i , F lo r id a . Am e ri ca n Di a be t es As so ci a ti o n. D i ab e te s
C a r e 19 9 8; 2 1: 1 55 1 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 5 9 . H a f fn e r S M e t a l . Re d uc e d co r o na r y e ve nt s i n s im va s ta t in - t re a te d p at i e nt s wi t h co r o na r y
h e a r t d is ea se an d d ia b e te s o r im pa i re d fa st i ng glu c os e l e vel s : su b gr o up an a l yse s i n t he
S c a nd in a vi an S im va st a tin S u r vi val S t ud y. A rc h Int e r n Me d 19 9 9; 1 59 : 26 6 1.
[ C r o ss R e f]
2 6 0 . S ac ks F M e t al . The e f fe ct of p ra va s ta t in on co r o na r y e ve nt s a f te r m yo c ar d ia l i n fa rc t io n i n
p a t ie n ts wi t h a ve r ag e c ho l es t e ro l l e vel s . C h ol es te r o l a nd R ec u r re n t E ve nt s Tr i al in ve s ti ga t o rs .
N E n g l J Me d 19 9 6; 3 35 :1 0 0 1.
[ C r o ss R e f]
2 6 1 . G o l db e rg R B e t al . C a r d io va sc u la r e ve n ts an d th e i r r ed uc t io n wi t h pr a va s ta t in in di a be t ic
a n d g lu c os e - i nt o le r an t myo c a r di al in f a rc ti o n su r vivo r s wi t h a ve ra ge ch ol est e r ol le ve l s:
s u bg r ou p a n a l ys es in the ch o le st e r ol an d r e cu r re n t e ve n ts ( C A R E ) t r ia l . Th e C a r e
I n ve s ti ga t o rs . Ci r cu la t ion 1 99 8 ;9 8 :2 5 13 .
[ F u ll t e xt L in k ]
2 6 2 . E l am MB e t al . Ef f ec t of ni ac i n o n li p id an d li p op r o te i n l e vel s a nd gl yc em i c co n t ro l i n
p a t ie n ts wi t h d ia b et e s an d pe r ip h e ra l a r te r i al di se a se : th e A D MI T s t u d y: A r a nd o mi ze d t r ia l .
A r t e r ia l Di se as e Mu l t ip l e I n t er ve n ti o n Tr i a l . J A MA 2 0 00 ; 28 4 :1 2 63 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 6 3 . G r u nd y S M e t a l . Eff i ca c y, s a fe t y, a n d t ol e r ab i li t y o f o nc e -d a il y ni a cin f o r t he t re a tm e nt of
d ys l ip id e mi a a ss oc ia t ed wi t h t yp e 2 d ia be t es : re su l ts o f t he as se ssm e nt of d ia b et es co n t ro l a nd
e va l u at io n of th e e f f ic acy o f n ia sp an t ri a l. A rc h In t e r n Me d 2 0 02 ; 16 2 :1 5 68 .
[ C r o ss R e f]
2 6 4 . A i el lo L P e t a l . D i ab e t ic re t in o pa t h y. D i ab e te s C ar e 1 9 98 ; 21 : 14 3 .
2 6 5 . F on g D S e t a l . D i abe t ic r et i no p at h y. D ia be t es C a re 20 0 4; 2 7 ( Su pp l 1 ): S 8 4 .
2 6 6 . V i ni k A et al . R ec ent a d van c e in t he di ag n osi s a n d t r ea tm e nt o f d ia bet i c n eu r o pa t h y.
E n d oc r in o lo gi s t 1 99 6 :4 43 .
2 6 7 . V i ni k A et al . G as t ro i n te st i na l , g en i to u ri n ar y, a nd ne u r o vasc u la l d is tu r n ba nc e s in
d i ab e te s . D i ab e te s Re vie w 1 9 9 9 :3 5 8.
2 6 8 . P a tt e rs o n D e t a l. A d o ub le - b li nd mu l ti ce n te r c om pa r is o n o f d om pe r i do n e a n d
m e to cl o p ra mi de in t he t re a tm e nt o f d ia be t ic pa t ien t s wi t h s ymp t oms o f g as t r op a re si s . A m J
G a s t r oe n te r ol 19 9 9; 9 4: 12 3 0 .
[ C r o ss R e f]
2 6 9 . B o ul t on AJ et al . Gu i de l in es fo r t he di ag n osi s a n d o ut p at i en t m an a ge m en t o f di ab e ti c
p e r ip h e ra l n eu r o pa t h y. D i a be t Me d 1 99 8 ;1 5 :5 0 8.
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 7 0 . Ma l i k R . P a th o lo g y a n d p a th o ge ne si s o f d i ab e t ic n e u ro pa t h y. Di a be te s R e vie w 1 9 9 9: 2 53 .
2 7 1 . B o ul t on AJ . C ur r e nt a n d em e r gi ng t re a tm e nt o f di ab e ti c n eu r o pa t hi es. D i ab e te s Re vi e w
1 9 9 9: 3 79 .
2 7 2 . B ac ko n ja M, G l a n zm a n R L . G ab ap e nt i n d osi n g f o r n e ur o pa t hi c p ai n : e vi d en ce f ro m
r a n do mi ze d , p la ce b o -c on t r ol l ed cl in ic a l t r ia ls . Cli n Th e r 2 0 03 ; 25 : 81 .
[ C r o ss R e f]
2 7 3 . B ac ko n ja M e t a l. Ga b a pe n ti n f o r t h e s ymp t om a ti c t r ea t me n t o f p ai n ful n e u r op a th y i n
p a t ie n ts wi t h d ia b et e s me l li t us : a r an d omi ze d c on t r ol l ed t ri a l. J A MA 1 9 9 8; 2 8 0: 1 83 1 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 7 4 . E is e nb e rg E e t al . La m ot r i gi ne r ed uc es pa i nfu l di ab e ti c n eu r o pa t h y: a r a n do mi ze d ,
c o nt r o ll ed st u d y. Ne u ro lo g y 2 00 1 ;5 7 :5 0 5.
[ F u ll t e xt L in k ]
2 7 5 . K l in e K M e t a l . P a inf u l d i ab e ti c p e ri ph e r al n eu r o pa t h y r el ie ve d wi t h us e o f or a l
t o p ir a ma t e. S ou t h Me d J 2 0 03 ; 96 : 60 2 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 7 6 . H a r at i Y e t a l . D o ubl e - bl i nd ra n do mi ze d tr i al o f t ra ma d ol fo r th e t re a tm e nt o f t he pa i n o f
d i ab e ti c n e ur o pa t h y. Neu r o lo g y 19 9 8; 5 0: 1 84 2 .
[ F u ll t e xt L in k ]
2 7 7 . H a r at i Y e t a l . Ma i n t e n an ce of t he lo ng - t e rm e f f ec ti ve n ess o f t r am ado l in t re a tm en t o f th e
p a in o f d ia be t ic ne u ro p ath y. J Di a be t es C om pl ic a ti o ns 20 0 0 ; 1 4: 6 5
[ C r o ss R e f]
2 7 8 . Me n d e ll J R , S ah e nk Z . C li ni c al p r ac t ic e . P ain f u l se ns o r y ne u r op a th y. N E n gl J Me d
2 0 0 3; 3 48 : 12 43 .
2 7 9 . L us ch e r TF e t a l . Dia b e te s a nd va sc ul a r d is ea s e: pa t ho p h ysi ol o g y, c lin i ca l c on se q ue nc es ,
a n d m ed ic a l t he r ap y: P ar t I I . C i rc u la t io n 2 0 03 ; 108 : 1 65 5 .
[ F u ll t e xt L in k ]
[ C r o ss R e f]
2 8 0 . Ma yf i e l d J A et al . Pr e ve n t i ve f oo t c a re in di ab e t es . Di a be t e s Ca r e 2 00 4 ; 27 ( S up p l 1 ) : S6 3 .
2 8 1 . S h il li n g F . F o ot c a re i n p at i en ts wi t h di ab e te s . Nu r s S t an d 2 0 03 ; 17 :6 1 , 6 6 , 6 8 .
2 8 2 . A D A P os it i on S ta t em e nt . As p ir i n Th e r a p y i n D i a be t es . Di a be t es Ca re 2 00 4 ;2 7 ( Su p pl
1 ) : S 72 .
2 8 3 . Mc Ma h o n M e t al . Ef f e ct s o f g lu c oc or t ic oi ds o n c a r bo h yd ra t e m et a bo li sm . D ia be t es Me t a b
R e v 1 9 88 ; 4 :1 7 .
[ C r o ss R e f]
2 8 4 . B r es sl e r P, D eF r o nzo R A . D r u gs a n d d ia b ete s . Di ab e t es Re vi e w 1 9 94 : 5 3.
2 8 5 . G o me z E C , F ro st P . I n du c ti on o f g l yc os u r ia a n d h yp e rg l yc em ia b y t op i ca l c o rt ic os t e ro id
t h e r ap y. A rc h De r ma t ol 1 9 7 6; 1 12 : 15 59 .
[ C r o ss R e f]
2 8 6 . D a vi es D , e d . Te xt b o o k o f Ad ve r se D r ug R ea c ti o ns , 3 r d E d . O xf o r d : O xf o r d U n i ve rs it y
P r e ss , 1 9 85 .
2 8 7 . B ak e r L et al . H yp er g l yc em ia an d a ce t on u ria si mu l at i ng di ab e te s . Ph e n yl ep h ri n e
a ss o ci at e d h yp e rg l yce mia a nd ac et o nu r ia si mu la ti n g d ia b et e s me ll i tu s . Am J D is C hi l d
1 9 6 6; 1 11 : 59 .
[ Me d l i n e L in k ]
2 8 8 . P o r te D , J r . S ym pa th e t ic re g ul a ti on o f in s ul in se c re t io n . I ts r el a ti o n to d ia be t es m e ll i tu s.
A r c h I n te r n Me d 19 6 9; 1 23 : 2 52 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 8 9 . Mc D o n a ld J. A lc oh ol a nd di ab e te s . D i ab e te s C a r e 1 9 80 ; 3: 6 29 .
[ Me d l i n e L in k ]
2 9 0 . F r an z MJ . D i a be t es m el l it us : c o ns id e ra t io ns i n t h e d e vel o pm en t o f gu i de l in es fo r t he
o cc a si on a l us e o f al co hol . J A m D i et A ss oc 1 9 83 ;8 3 : 14 7 .
[ Me d l i n e L in k ]
2 9 1 . F a rk as - H i rsc h R . I nt e ns i ve Di a be t es Ma n a ge m en t . Al e xa n d r ia , V A: A m e ri c an D ia be t es
A s so ci a ti o n, I nc ., 19 9 5 :57 .
2 9 2 . V a ag A e t a l . Va r ia ti o n i n a bs o rp t io n o f N P H i ns u li n d ue t o i nt r am us cu l a r i nj ec t io n .
D i a b et es C a re 19 9 0; 1 3: 74 .
[ C r o ss R e f]
2 9 3 . Th o w J C e t a l . E f fec t of r ai si ng in j ec ti o n -s ite sk in t em pe r a tu r e o n iso p h an e ( N P H ) in su l in
c r ys t al di ss oc ia t io n . D i ab e t es C ar e 1 9 89 ; 12 : 43 2 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 9 4 . S a l zm a n R e t a l. In tr a n as al ae r os o li ze d i ns uli n . Mi xe d - m e a l st u di es an d lo ng - t e rm u s e in
t yp e I d i ab e te s. N E ng l J Me d 1 9 8 5; 3 12 : 10 7 8.
2 9 5 . F r au ma n A G e t a l . L o n g - t e rm u s e o f i nt r a nas a l i ns ul in in in su l in - de pe n d en t d i ab e ti c
p a t ie n ts . Di ab e te s Ca r e 1 9 8 7; 1 0: 5 73 .
[ C r o ss R e f]
[ Me d l i n e L in k ]
2 9 6 . K o i vis to V A . V a r io us in f lu e nc es o n i ns u li n ab s o rp t io n . N e th J Me d 19 8 5 ;2 8 ( Su p pl 1 ): 2 5.
2 9 7 . S e la m JL , C ha r le s MA . D e vi c e s fo r i ns u li n ad m in is t r at io n . Di a be t es C a r e 19 9 0; 1 3: 9 55 .
[ C r o ss R e f]
2 9 8 . E l i Li l l y & Co mp a n y. O r i gi n al l y in G al l o wa y J A e t al , ed s. D ia b et e s Me l l i t u s, 9t h Ed .
I n d ia na p ol is , I N : E li Li ll y & C o mp an y, 1 98 8 .
2 9 9 . A D A . N ut r i ti on r ec om me n da t io ns an d p r in ci pl e s f o r p eo p le wi t h d i ab et e s m el li t us .
D i a b et es C a re 20 0 1: 2 4 (S u p pl 1 ): S 4 4.
3 0 0 . H o w t o in j ec t yo u r in s ul in . P at i en t e d uc at i on p am p hl e t # 00 0 -1 8 0p l No vo N o r di sk
P h a r ma ce u ti ca ls In c ., 199 5 .