Insulin and Non Insulin
Treatments of Diabetes Mellitus
Orla Mahony
March 2012
Non-insulin treatments
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Sulfonylureas
Biguanides
Chromium and vanadium
Acarbose
Incretinmimetics
Amylin
Sulfonylureas (Glipizide)
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Enhance insulin secretion
Bind to the KATP channel on ß cell
Glipizide in 50 diabetic cats; Feldman 1997
Improvement in 30% of new DM cats
Side effects; hypoglycemia, vomiting, inc LE’s and icterus
(<15%)
Recommend for owners unable to give insulin, or for cats with
intermittent transient DM or for cats exquisitely sensitive to
insulin
Glipizide may increase amyloid deposition,Hoenig et al, 2000
Regulation of Insulin Secretion
Sperling M. N Engl J Med 2006;355:507-510
Schematic Representation of the Pancreatic Beta Cell, Illustrating the Role of the ATP-Sensitive
Potassium (KATP) Channel in Insulin Secretion
Gloyn A et al. N Engl J Med 2004;350:1838-1849
Biguanides
(Metformin/Glucophage)
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Increases translocation of GLUT 1 & 4 transporters in different
types of cells
Inhibits hepatic gluconeogenesis and glycogenolysis
Increases muscle glucose metabolism by enhancing muscle
insulin sensitivity
Does not stimulate insulin secretion (no hypoglycemia)
Can rarely cause (fatal) lactic acidosis by stimulating intestinal
conversion of glucose to lactate
Decreased hepatic synthesis of VLDL
Metformin & sulfonylureas produce similar results
Weight gain rare with metformin
Metformin in Cats
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Nelson et al, JVIM 2004
Study involved normal and diabetic cats
Disappointing results, 3 failed to respond and
1 died
Death undetermined
Side effects included lethargy, inappetence,
vomiting, and weight loss
Chromium and Vanadium
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Transition-metals
Activate glucose metabolism within the cell
Insulin sensitizers
Chromium is an essential cofactor for insulin function and
chromium deficiency results in insulin resistance
Schachter et al 2001; Chromium had no effect in diabetic dogs
Appleton DJ et al 2002; Improved glucose tolerance in normal
weight, healthy cats given chromium
Greco D states low doses of vanadium (0.2mg/kg/day)
lowers glucose and fructosamine in early T2DM cats
Transient anorexia
Long term accumulation could lead to CRF (1 cat)
Acarbose
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Complex oligosaccharide of microbial origin
Competitively inhibits α-glucosidases in GIT
Acarbose improved glucose control in 6 diabetic
dogs but ⅓rd had diarrhea and weight loss
Nelson et al 2000
Diabetic cats fed a low CHO diet had a similar
response to cats on low CHO diet and acarbose
Mazzaferro et al JFMS 2003
Incretin Hormones
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Incretins
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GIP, glucose-dependent insulinotropic
polypeptide
GLP-1, glucagon like peptide 1
Incretin effect
Oral GTT versus i/v GTT
The incretin effect is the increased insulin
secretion which occurs with food ingestion
as a result of release of incretin hormones,
primarily GIP and GLP-1.
GIP Glucose-dependent insulinotropic
polypeptide
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Secreted by K cells of duodenum in response to
food
Primary action is stimulation of glucosedependent insulin secretion
May stimulate β cell proliferation and inhibit
apoptosis
Inactivated by Dipeptidyl-peptidase IV (T½ 7
mins)
Glucagon-like peptide 1 GLP-1
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Produced by L-cells (primarily distal SI)
Secreted in response to nutrient ingestion
Stimulates glucose-dependent insulin
secretion (via G protein coupled R, ↑ cAMP,
↑ iCa, exocytosis)
Effect on insulin secretion may also be via
autonomic nerves
βcell proliferation and neogenesis in rodents
Inhibits apoptosis in human tissue cultures
Extensively metabolized by the enzyme
DPP-4
Other Actions of GLP-1
 Inhibits glucagon secretion
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Delays gastric emptying
Reduces food intake
Cardioprotective effects
Renal protective effects
Modulatory role in HPit axis?
Incretins in cats
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GLP-1 secretion is stimulated by glucose,
amino acids and lipids
K and L cells throughout small and large GI
Potentiation of insulin secretion is minimal
with oral glucose and is mediated by GLP-1,
not GIP
GIP secretion is stimulated by amino acids
and lipids
DPP-4 / CD26
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Serine protease
Degrades GLP-1 and GIP
Ubiquitous in tissues and blood
Only 15% active form reaches systemic
circulation, therefore need to measure active
and inactive forms (total) to evaluate GLP -1
secretion
GIP more than GLP also degraded renally
Loss of the incretin effect in T2DM and
obesity
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Loss of β cell response to GIP
Decreased secretion of GLP-1 (2° to DM)
Impaired β cell sensitivity to GLP-1
Glucose stimulated GLP-1 concs. higher in
lean vs obese cats, Hoenig 2010
Implications
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Treatment with GIP unhelpful
Treatment with native GLP-1 unhelpful (T1/2
2 mins)
Treatment with GLP-1 analogs
Dipeptidyl peptidase-4 inhibitors
GLP-1 mimetics
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Exenatide (Byetta), synthetic exendin-4
8 hr DOA, biologic effects up to 15 hrs
Restores early insulin response
As effective as insulin glargine but fewer side
effects
One report of pancreatitis
Antibody formation common
Promotes beta cell regeneration and
differentiation (rats)
Amylin/Pramlintide
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Synthetic analog of amylin (IAPP) that does not form
amyloid
Approved for treatment of T1 and T2 DM 2005
Slows gastric emptying
Suppresses post prandial hyperglycemia
Decreases postprandial hyperglucagonemia
Improves glycosylated Hb concn
Weight loss (desirable)
Side effects include nausea and hypoglycemia
Amylin in cats
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Amylin reduces glucagon in normal cats
Vet Journal 2009, Furrer et al
Study used rat amylin, and showed mild
decreases in glucagon following arginine,
glucose and meal stimulation.
Short acting
May be more beneficial in diabetic cats
Insulins
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Humulin NPH U100
Insulin glargine/Lantus U100
Detemir U100
PZI U40
Porcine Lente U40
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All mammalian insulin is similar
51 AA’s in 2 polypeptide chains
21 AA A-chain
30 AA B chain
Formulation
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Short-acting
Intermediate-acting
Long-acting
Sometimes mixed together
Do not mix glargine or Zn insulins
with other insulins
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Lentes (semilente, lente, ultralente) all have _____
to delay absorption
NPH has _____ to delay absorption
PZI has _____ and _____ to delay absorption
1 unit of insulin = 36 mcg of insulin
Use U40 syringes with U40 insulin (40 IU/ml)
Vetsulin (porcine lente) and PZI are U40 (40 IU/ml)
insulins
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½ unit scale syringes are available
(diabetes care, 31g, 30u short needle)
Vial syringe guides
Syringe magnifiers
Keith et al showed drawing up 1-2 unit
doses inaccurate with syringes
Humulin NPH U100 / Isophane
(neutral protamine Hagedorn)
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Contains fish protein, protamine, to delay absorption
Intermediate insulin
Recommended for dogs
Give BID
Goeders et al 1987; dogs
Time for NPH to return to baseline; 8 hrs
Wallace et al 1990; cats
Peak insulin concentraton 1.6 hrs, DOA 7.7 hrs.
Humulin NPH in diabetic dogs
Palm et al JVIM 2009;23:50-55
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10 well controlled DM dogs, <1U/kg bid, fed
high fiber diets (wd 7, euk wt control 3, nutro wt
control)
BG and insulin measured q 30mins for 2hrs,
then q 2hrs for up to 10hrs
Insulin DOA 4-10hrs (T0 bg to time for bg to
reach 70% of baseline), 4 dogs ≥ 10 hrs
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Mean % of insulin-induced glucose
suppression 50%
Post-prandial hyperglycemia in 5 dogs,
resolved within 2.2hrs
Insulin Glargine/Lantus
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Human recombinant insulin with AA
substitutions and additions
Shift in isoelectric pt.,soluble at pH 4
Insulin precipitates into hexamers at
interstitial pH of 7.4
Hexamers slowly form active insulin
monomers
Gradual onset, long duration
Insulin glargine/Lantus
Insulin Glargine/Lantus
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Glucose nadir healthy cats; glargine (14 hrs), PZI
(biphasic 4, 14 hrs), lente (5 hrs)
Marshall et al, J vet Pharmacol Therap 2008
SID not inferior to bid in normal cats, Marshall 08
BG suppressed @ 24 hrs in 1/2 of sid or bid cats
Higher remission rate with glargine (8/8) vs PZI (3/8)
vs lente (2/8) newly dx diabetics, dm canned diet
Marshall et al, JFMS 2009
Glargine SID is as effective as lente BID
Weaver et al, JVIM 2006
Use of insulin glargine in dogs
with DM Fracassi Vet Rec 2012
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12 dogs, 9 new diabetics, 3 tx with vetsulin
3 intact females (spayed within 3 wks)
Glargine; 0.27 U/kg (0.18-0.53) at start and
0.6 U/kg (0.11-1.07) at end
Nadir varied (0-12), 6, 8, 10 hrs on average
BG<90 in 18% of curves, no clinical hypogly
Varied diet
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BGCs done before, 1, 2, 4, 8, 12, 24 weeks
12 hr curves, dog usually fed and inj. @ hosp
58% good control (mean bg < 230)
33% moderate control (mean bg 230-300)
1% poor control (mean bg >300)
Fructosamine (good 25%, moderate 58%,
poor 17%)
Discussion
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Results similar to NPH and vetsulin studies
although vetsulin study stated 75% good
control
No clinical hypoglycemia
Clear nadir (unlike in people, peakless) but
unpredictable
May have needed 24 hr curve to determine
nadir
Insulin Detemir/Levemir®
U100 Insulin
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Approved in US 2006
Long-acting,synthetic insulin analogue
Similar to glargine
Slow release due to formation of hexamers as well as
binding to albumin at the injection site and in the
circulation( inc. availability to liver w fenestrated
vessels)
More consistent glucose lowering than with lantus
Reduced risk of hypoglycemia?
2 studies of use in cats
Max dose 30% lower than lantus, rarely > 4U
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Detemir is acetylated with myristic
acid(saturated FA found in dairy products),
allowing hexamers to form at a neutral pH,
and importantly allowing the insulin to bind to
albumin, resulting in a very slow, smooth
delivery of insulin such that once daily
administration is all that is needed in people
ProZinc™
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Protamine zinc recombinant-human insulin
U40 insulin, use with U40 syringes
Preliminary study of PZIR for the Tx of DM in
cats Vet Ther 2009;10:24-28
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50 cats, switched from PZI VET to PZIR same dose
and interval, no significant differences in wt, fruct
days 15, 30 compared to day 0.
Field safety and efficacy of PZIR bid
for Tx of DM in cats JVIM
2009;23:787-793
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133 cats, 13 previously diagnosed
9hr bg curve done day 0, 7, 14, 30, 45. Fruct
done day 0, 14, 30, 45
Hypoglycemia (<80) detected in 64% of cats
Clinical signs in 2, possibly 26 other episodes
On day 45, 34% of cats had low glu nadir, mean
bg or fruct on day 45, some were probably going
into remission
Bid admin, nadir 5-7, bg increasing by 9hrs
PZI and Dogs?
Pharmacokinetics and Pharmacodynamics of Glargine, Beef-Pork
PZI & Pork Lente Insulin in Healthy Dogs Stenner ACVIM abs 2004
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Onset of Action; lente (0.6 hr), PZI (3 hrs) Glargine (2.2 hrs)
Glucose Nadir; lente (2.4 hrs) glargine (5.7 hrs) PZI (6.4 hrs)
DOA lente (10 hrs) glargine (13 hrs), PZI (19 hrs)
Peak insulin; lente (1.2 hrs), glargine (0.5-6 hr), PZI (0.5 hr)
Glargine had no glucose lowering effect in 2/9 dogs
Glargine unpredictable in dogs
PZI glucose lowering effect in 9/9 dogs but Ab’s to beef insulin
a potential concern
Efficacy of rhPZI in dogs with DM
Maggiore et al JVIM 2012
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6 new diabetics, 11 previous diabetics
10 hr bg curve day 7, 14, 30, 60
Fructosamine, spec cPL
0.25-0.5 U/kg initial dose
Goal; bg between 80-300, nadir 80-150
Results
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LBG10h 80-150 n= 4, >200 n=11, <80 n=2
No significant change betw day 1 and 60
LBG10h >200 in 42 of 68 bg curves
LBG10hr occurred 2-12 hrs post inj, and in
54% was at start or end of curve
7 hypoglycemic events (3 clinical, 4
nonclinical during curves)
Results
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MBG 299±115 vs 457±38
MBG decreased in 16 dogs
Fructosamine 478±83, vs 557±104
Fruct decreased in 11/17 dogs
PuPd improved in 14Body wt stable or
increased in 16
Inconsistency in BG concs from
day to day
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Prolonged duration of rhPZI effect
Somogyi response
Pharmacokinetic variability of rhPZI
Once daily administration?
High dose requirements
Starting dose of 0.5U/kg
Median end dose of 1U/kg (0.4-1.5)
Porcine Lente Insulin
(Vetsulin) U40
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40 IU/ml
Mixed insulin Zn suspension
30% amorphous semilente rapidly absorbed
70% crystalline Zn ultralente slowly absorbed
Intermediate insulin
Licensed for use in dogs
Less potent than NPH but longer acting
Vetsulin continued
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DOA 14 to 24 hrs
Many dogs have 2 peaks (4, 11 hrs) of
insulin activity (Graham et al, JSAP 1997)
In some dogs earlier peak is largest
Dose ¼ to ½ u/kg SQ BID
U40; more accurate dosing in small dogs
Administer BID (Munroe et al, JVIM 2005)
(Horn et al, Aust Vet J 2001)
Vetsulin in Cats
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Parmacology of Vetsulin in diabetic cats
Martin et al, JFMS 2001
Time to peak insulin 2 hrs
Time to glucose nadir 4 hrs
Time for insulin concentration to return to baseline – 8 hrs
Give BID (may even need TID)
Similar pharmacological properties to beef-pork NPH
Shorter DOA compared with Humulin and beef/pork UL and
beef-pork PZI
Antibodies to porcine insulin possible
Poor absorption possible
Amino Acid Differences between
species
Dog
Pig
Human
Cow
Cat
A8
Thr
Thr
Thr
Ala
Ala
A10
Ile
Ile
Ile
Val
Val
A18
Asn
Asn
Asn
Asn
His
B30
Ala
Ala
Thr
Ala
Ala
Feldman & Nelson 3rd Ed p496