Intensive Insulin Therapy
Robert E. Jones, MD, FACP, FACE
Professor of Medicine
University of Utah School of Medicine
Objectives
1. Define intensive insulin therapy
2. Explore the basis of insulin therapeutics:
•
•
Insulin dosing (just where did the “Rule of 1700”
come from and how does it relate to my patients?)
Insulin kinetics
3. Discover how to modify a mathematically crafted
(and otherwise perfect) insulin regimen to match
the needs of our patients
4. Understand that nothing is perfect
Intensive Insulin Therapy
Physiologic Insulin Therapy
Insulin Effect
Bolus insulin
Basal insulin
B
L
D
HS
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Marcel Dekker, Inc; 2002:193
Biological Actions Of
Insulin
• Glucose lowering
• Anabolic properties
– Storage of lipids, protein, carbohydrate
•
•
•
•
•
Anti-catabolic properties
Mitogenic properties
Growth factor
Promote endothelial function
Anti-inflammatory
Basic Insulin Regimen: SplitMixed Regimen or Premix
Endogenous insulin
Regular
NPH
B
L
D
HS
B
Basal vs Bolus Insulin
BASAL INSULIN
BOLUS INSULIN
• Suppress hepatic glucose
production (overnight and
intermeal)
• Prevent catabolism (lipid
and protein)
– Ketosis
– Unregulated amino
acid release
• Reduce glucolipotoxicity
• Meal-associated CHO
disposal
• Storage of nutrients
• Help suppress inter-meal
hepatic glucose production
The Mathematics
The Systems
• Accurate Insulin Management
– Rule of 1700
– CIR
• Body Weight Only
– Assumes insulin requirements are predicted
only on the basis of weight
• 400/500 Rule
– CIR = 400-500/TDD
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Accurate Insulin
Management
• Combines 1700 Rule and Rule of 3
• 1500 Rule (Davidson, 1983)
– Refined as 1700 Rule
– CF = 1700/TDD
• Rule of 3 (Steed, 1998)
– CIR = 3 * BWlb/TDD
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Regression Models
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
AIM Equations
• When insulin requirements are known:
– CF = 1700/TDD
• Glucose lowering per unit of insulin
– CIR = 2.8 * BWlb/TDD
• G rams CHO covered per unit of insulin
– Basal = 0.47 * TDD
• When insulin requirements are NOT known
– TDD = 0.24 * BWlb
Davidson PC et al. Endocr Pract 14:1095-1101 (2008)
Simple Equations
• TDD = Basal + Bolus (50:50)
• CF = 1700/TDD
• CIR = 0.33 * CF
UDPRs, 2008
IHC Diabetes Care Model, 2010
Comparisons
25 year old 150 lb woman who requires 30 U/day
Parameter
Simple
AIM
400/500
Eqn
Result
Eqn
Result
Eqn
Result
Basal
TDD*0.5
15
TDD*0.47
14.1
TDD*0.5
15
CF
1700/TDD
56.7
1700/TDD
56.7
1700/TDD
56.7
CIR
CF*0.33
1:18.7
2.8*BWlb/
TDD
1:14
441/TDD
1:14.7
Comparisons
25 year old 150 lb woman who requires 50 U/day
Parameter
Simple
AIM
400/500
Eqn
Result
Eqn
Result
Eqn
Result
Basal
TDD*0.5
25
TDD*0.47
23.5
TDD*0.5
25
CF
1700/TDD
34
1700/TDD
34
1700/TDD
34
CIR
CF*0.33
1:11.2
2.8*BWlb/
TDD
1:8.4
441/TDD
1:8.8
Comparisons
45 year old 200 lb man who requires 110 U/day
Parameter
Simple
AIM
400/500
Eqn
Result
Eqn
Result
Eqn
Result
Basal
TDD*0.5
55
TDD*0.47
51.7
TDD*0.5
55
CF
1700/TDD
15
1700/TDD
15
1700/TDD
15
CIR
CF*0.33
1:5.0
2.8*BWlb/
TDD
1:5.1
441/TDD
1:4.0
Comparison Conclusions
• Equations assume everyone is average
– There is a wide variability that defines
“average”
• Basal insulin requirements
– No significant differences
• Bolus requirements
– The “Simple Method” seems to under estimate
CIR in more insulin-sensitive patients
Insulin Kinetics
Euglycemic
Hyperinsulinemic Clamp
Because
HGO
is insulin
suppressed
and at
glucose
are clamped,
the rate
of
AnHGO
IV bolus
is effectively
of
suppressed
is given
(in
time
normals)
0levels
followed
and
an
byexogenous
a constant
infusion
glucose
2. Yields
exogenous
musttarget
equal
the rate
of tissue
glucose
uptake.
infusion
isglucose
started
to
glucose
levels.
Labeled
glucose
may
of
1 mU/min/kg
orinfusion
40maintain
mU/min/m
insulin
levels
of ~ 70
U/mL.
be used to completely assess endogenous glucose production.
48
90
70
50
Insulin (U/mL)
Glucose (mg/dL)
80
36
40
24
12
0
0
60
Time (min)
80
Glucose Infusion Rate
(mol/minkg)
110
Analog Insulin Profiles
Aspart, Lispro, Glulisine (4–5 hr)
Regular (6–10 hr)
Plasma Insulin Levels
NPH (10–20 hr)
Detemir ~18-24hr Glargine (~24 hr)
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (hr)
Rosenstock J. Clin Cornerstone. 2001;4:50-61.
What Can Influence Insulin
Kinetics?
Effect of Dose (Lispro)
(PK)
Obese 50 U
Healthy 10 U
Obese 30 U
Obese 10 U
Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.
Effect of Dose (Lispro)
(PD)
Healthy 10 U
Obese 30 U
Obese 50 U
Obese 10 U
Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.
Effect of Dose (Detemir)
Detemir
0.2 U/kg
1.6 U/kg
0.8 U/kg
0.4 U/kg
NPH 0.3 IU/kg
0.1 U/kg
Plank J et al. Diabetes Care 28:1107-1112 (2005).
Effect of Premixing on RapidActing Analog Properties
Plasma Insulin Levels
Tmax 49-53 min
Tmax 2.4 hours
-60
0
Aspart 1,2
70/30 NovoLog Mix 3
60 120 180 240 300 360 420 480 540
Time (min)
1. Hedman CA et al. Diabetes Care 2001;24:1120-1121
2. Home PD et al. Eur J Clin Pharm 1999;55:199-201
3. Novo Nordisk, data on file
90
Plasma Glucose
80
mg/dl
70
5.0
4.5
4.0
24
PEN DOWN
20
3.0
16
0.3 U/Kg NPH s.c.
MIX
12
2.0
8
1.0
4
PEN UP
0
0
0
Lepore M. et al., unpublished data
1 2
3 4
5 6
Time (hours)
7
8 9
µmol/Kg/min
Glucose Infusion Rate
mg/Kg/min
4.0
mmol/l
Effect of Insulin
Suspensions on GIR
What Else Can Influence
Insulin Kinetics?
• Site of injection
• Local blood flow
– Exercise
– Obesity
• Inherent variability
• Absentmindedness
• Effect of food
Effect of Food
Or Think Outside
the Box...
Mondo
Mondo
Mama’s
Mama’sPizza
Pizza
Effect of Food
Mondo
Mondo
Mama’s
Mama’sPizza
Pizza
Or Think Outside
the Box...
DUAL WAVE
BOLUS
Effect of Food
Or Think Outside
the Box...
Mondo
Mondo
Mama’s
Mama’sPizza
Pizza
RAA + RHI
(50/50 Mix)
Difficult Questions That
Were Not Asked
• When do you split the basal insulin?
– NPH
– Detemir
– Glargine
• How do you time a bolus in relationship to
eating?
Cases
Case #1
45 year old man is seen with complaints of polyuria
and polydipsia of several weeks duration. He has
had an associated 30 lb weight loss. He weighs
250 pounds.
Lab results:
RBS 397 mg/dl; A1C 12.6%; Na+ 133 mEq/l; CO2
19 mEq/L
What does he have and how would you treat him?
Case #1
• The practice of medicine is an art…but we
base our decisions on science (and
experience)
• Oral agents?
• Insulin?
– Premix
– Basal only
– Basal-bolus
Case #2
56 year old woman returns for follow up. She has
had diabetes for 10 years and has intermittently
struggled with her glucose control (A1C range 6.4
-8.8%). Her current A1C is 8.9% and her fasting
glucose (SMBG) is 210 mg/dL. She is presently
taking metformin 1500 mg/d, glyburide 15 mg/d;
sitagliptin 100 mg/d, exenatide 10 mcg BID
How would you alter her therapy?
If you chose insulin, how would you start it?
Case 2
Secretogogue
Insulin Effect
Metformin
B
L
D
HS
Basal Insulin
Case 3
A 25 year old woman is sent to you because
her glucose control is poor (A1C 9.7%).
She really wants to improve her control,
but doesn’t know how, and, by the way, she
is recently married.
She is currently on 25 IU glargine per day and
5 to 15 IU aspart given before meals. She
tests her glucose levels 3-4 times a day.
Florentine Arch
Hypoglycemia
Severe insulin reactions per 100 patient-yr
0
20
40
VA IIIP
100
120
110
SDIS
VA CSDM
80
62
DCCT
UKPDS
60
Type 1
diabetes
2.3
Type 2
diabetes
3
7.8
Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:
Marcel Dekker, Inc.; 2002:193
Weight v Delta A1C
Studies with Type 2 Diabetes
Glargine
NPH
Detemir
Reduction in A1C (%)
1. Yki-Jarvinen
Diabetes Care
2000;23:1131
2. Rosenstock
Diabetes Care
2001;24:631
3. Riddle Diabetes
Care 2003;26: 3079
4. Fritsche Ann Int
Med 2003;138: 952
5.Raslova Diab Res
Clin Pract
2004;66:193
6. Haak Diab Obes
Clin Pract 2005;7:56
7. Study 1530
8. Study 1337
9. Study 1373;
Rosenstock, 2006
2
7
7
3
3
1.5
9
9
8
4
8
1
1
0.5
2
5
2
4
1
5
2
6
6
0
1
2
3
Weight Gain (kg)
4