Intensive Insulin Therapy

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Intensive Insulin Therapy

• Robert E. Jones, MD, FACP, FACE
• Professor of Medicine
• University of Utah School of Medicine

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Objectives

• Define intensive insulin therapy
• 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
• Discover how to modify a mathematically crafted
  (and otherwise perfect) insulin regimen to match
  the needs of our patients
• Understand that nothing is perfect

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Intensive Insulin Therapy
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Physiologic Insulin Therapy
Bolus insulin
Basal insulin
Insulin Effect
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B
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HS
Adapted with permission from McCall A. In
Insulin Therapy. Leahy J, Cefalu W, eds. New
York, NY Marcel Dekker, Inc 2002193
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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

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Basic Insulin Regimen Split-Mixed Regimen or
Premix
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Basal vs Bolus Insulin

• BOLUS INSULIN
• Meal-associated CHO disposal
• Storage of nutrients
• Help suppress inter-meal hepatic glucose
  production

• BASAL INSULIN
• Suppress hepatic glucose production (overnight
  and intermeal)
• Prevent catabolism (lipid and protein)
• Ketosis
• Unregulated amino acid release
• Reduce glucolipotoxicity

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The Mathematics
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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 141095-1101
(2008)
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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 141095-1101
(2008)
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Regression Models
Davidson PC et al. Endocr Pract 141095-1101
(2008)
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Regression Models
Davidson PC et al. Endocr Pract 141095-1101
(2008)
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Regression Models
Davidson PC et al. Endocr Pract 141095-1101
(2008)
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Regression Models
Davidson PC et al. Endocr Pract 141095-1101
(2008)
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Regression Models
Davidson PC et al. Endocr Pract 141095-1101
(2008)
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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 141095-1101
(2008)
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Simple Equations

• TDD Basal Bolus (5050)
• CF 1700/TDD
• CIR 0.33 CF

UDPRs, 2008 IHC Diabetes Care Model, 2010
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Comparisons
25 year old 150 lb woman who requires 30 U/day
Parameter Simple Simple AIM AIM 400/500 400/500
Parameter Eqn Result Eqn Result Eqn Result
Basal TDD0.5 15 TDD0.47 14.1 TDD0.5 15
CF 1700/TDD 56.7 1700/TDD 56.7 1700/TDD 56.7
CIR CF0.33 118.7 2.8BWlb/TDD 114 441/TDD 114.7
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Comparisons
25 year old 150 lb woman who requires 50 U/day
Parameter Simple Simple AIM AIM 400/500 400/500
Parameter Eqn Result Eqn Result Eqn Result
Basal TDD0.5 25 TDD0.47 23.5 TDD0.5 25
CF 1700/TDD 34 1700/TDD 34 1700/TDD 34
CIR CF0.33 111.2 2.8BWlb/TDD 18.4 441/TDD 18.8
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Comparisons
45 year old 200 lb man who requires 110 U/day
Parameter Simple Simple AIM AIM 400/500 400/500
Parameter Eqn Result Eqn Result Eqn Result
Basal TDD0.5 55 TDD0.47 51.7 TDD0.5 55
CF 1700/TDD 15 1700/TDD 15 1700/TDD 15
CIR CF0.33 15.0 2.8BWlb/TDD 15.1 441/TDD 14.0
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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

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Insulin Kinetics
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Euglycemic Hyperinsulinemic Clamp
Because HGO is suppressed and glucose levels are
clamped, the rate of exogenous glucose infusion
must equal the rate of tissue glucose uptake.
An IV bolus of insulin is given at time 0
followed by a constant infusion of 1 mU/min/kg or
40 mU/min/m2. Yields insulin levels of 70
?U/mL.
HGO is effectively suppressed (in normals) and an
exogenous glucose infusion is started to maintain
target glucose levels. Labeled glucose may be
used to completely assess endogenous glucose
production.
80
48
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Glucose Infusion Rate (?mol/min?kg)
40
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Insulin (?U/mL)
12
0
80
60
0
Time (min)
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Analog Insulin Profiles
Regular (610 hr)
NPH (1020 hr)
Plasma Insulin Levels
2
4
6
8
12
14
16
18
20
22
24
0
10
Time (hr)
Rosenstock J. Clin Cornerstone. 2001450-61.
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What Can Influence Insulin Kinetics?
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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.
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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.
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Effect of Dose (Detemir)
Detemir
1.6 U/kg
0.2 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 281107-1112 (2005).
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Effect of Premixing on Rapid-Acting Analog
Properties
Tmax 49-53 min
Tmax 2.4 hours
Plasma Insulin Levels
Time (min)
1. Hedman CA et al. Diabetes Care
2001241120-1121 2. Home PD et al. Eur J Clin
Pharm 199955199-201 3. Novo Nordisk, data on
file
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Effect of Insulin Suspensions on GIR
90 80 70
5.0 4.5 4.0
Plasma Glucose
mmol/l
mg/dl
Glucose Infusion Rate
0.3 U/Kg NPH s.c.
Lepore M. et al., unpublished data
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What Else Can Influence Insulin Kinetics?

• Site of injection
• Local blood flow
• Exercise
• Obesity
• Inherent variability
• Absentmindedness
• Effect of food

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Effect of Food
Or Think Outside the Box...
Mondo Mamas Pizza
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Effect of Food
Or Think Outside the Box...
Mondo Mamas Pizza
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Effect of Food
Or Think Outside the Box...
Mondo Mamas Pizza
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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?

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Cases
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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?

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Case 1

• The practice of medicine is an artbut we base
  our decisions on science (and experience)
• Oral agents?
• Insulin?
• Premix
• Basal only
• Basal-bolus

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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?

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Case 2
Metformin
Basal Insulin
Secretogogue
Insulin Effect
HS
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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 doesnt 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.

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Florentine Arch
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Hypoglycemia
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Weight v Delta A1CStudies with Type 2 Diabetes
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Detemir
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1. Yki-Jarvinen Diabetes Care 2000231131
2. Rosenstock Diabetes Care 200124631
3. Riddle Diabetes Care 200326 3079
4. Fritsche Ann Int Med 2003138
952 5.Raslova Diab Res Clin
Pract 200466193 6. Haak Diab Obes
Clin Pract 2005756
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3
1.5
9
9
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Reduction in A1C ()
1
8
4
1
1
2
5
5
0.5
2
2
6
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7. Study 1530 8. Study 1337 9.
Study 1373 Rosenstock, 2006
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1
2
3
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Weight Gain (kg)
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Insulin Self Association Sites