Intensive Insulin Therapy Robert E. Jones, MD, FACP, FACE Professor of Medicine University of Utah...

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

Insu

lin E

ffe

ct

B DL HS

Bolus insulinBasal insulin

Physiologic Insulin Therapy

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: Split-Mixed Regimen or Premix

Regular

NPH

B DL HS B

Endogenous insulin

Basal vs Bolus Insulin

BASAL INSULIN• Suppress hepatic glucose

production (overnight and intermeal)

• Prevent catabolism (lipid and protein)– Ketosis– Unregulated amino

acid release• Reduce glucolipotoxicity

BOLUS INSULIN• 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


Regression Models


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


Simple Equations

• TDD = Basal + Bolus (50:50)

• CF = 1700/TDD

• CIR = 0.33 * CF

UDPRs, 2008IHC Diabetes Care Model, 2010

Comparisons

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

25 year old 150 lb woman who requires 30 U/day

Comparisons



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

25 year old 150 lb woman who requires 50 U/day

Comparisons

45 year old 200 lb man who requires 110 U/day



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

Glu

cose

(m

g/dL

)

110

70

50

90

80

40

0

Insu

lin

(U

/mL

)

48

36

24

12 Glu

cose

Inf

usio

n R

ate

(m

ol/m

ink

g)

Time (min)80600

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.

Because HGO is suppressed and glucose levels are clamped, the rate of exogenous glucose infusion must equal the rate of tissue glucose uptake.

Analog Insulin Profiles

Rosenstock J. Clin Cornerstone. 2001;4:50-61.

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sma In

sulin

Levels

Time (hr)

NPH (10–20 hr)

Regular (6–10 hr)

Glargine (~24 hr)

Aspart, Lispro, Glulisine (4–5 hr)

Detemir ~18-24hr

What Can Influence Insulin Kinetics?

Effect of Dose (Lispro) (PK)

Healthy 10 U

Obese 50 U

Obese 30 U

Obese 10 U

Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.

Effect of Dose (Lispro) (PD)

Obese 10 U

Healthy 10 U

Obese 50 U

Obese 30 U

Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.

Effect of Dose (Detemir)

Plank J et al. Diabetes Care 28:1107-1112 (2005).

Detemir

NPH 0.3 IU/kg

0.2 U/kg

0.1 U/kg

0.4 U/kg

0.8 U/kg

1.6 U/kg

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

Time (min)-60 0 60 120 180 240 300 360 420 480 540

Aspart 1,2

Pla

sma

Insu

lin

Lev

els

Effect of Premixing on Rapid-Acting Analog Properties

Tmax 49-53 min

70/30 NovoLog Mix 3Tmax 2.4 hours

mg/dl

0.3 U/Kg NPH s.c.

Plasma Glucose908070

5.0

4.5

4.0 mm

ol/l

Lepore M. et al., unpublished data

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

0 1 2 3 4 5 6 7 8 9Time (hours)

µm

ol/K

g/m

in

mg/

Kg/

min

PEN UP

PEN DOWN

MIX

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

Mondo Mama’s Pizza

Or Think Outside the Box...


Effect of Food



DUAL WAVE BOLUSMondo

Mama’s Pizza

Effect of Food



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?

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?

B DL HS

Insu

lin E

ffe

ct

Metformin Basal InsulinSecretogogue

Case 2

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

7.8

3

2.3

110

62

0 20 40 60 80 100 120

VA IIIP

VA CSDM

UKPDS

SDIS

DCCT Type 1 diabetes

Type 2 diabetes

Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193

0.5

0

1

1.5

2

Weight v Delta A1C

Studies with Type 2 Diabetes

1 2 3 4

Glargine

NPH

1

14

2

2

3 3

4

2

6

5

6

5

Detemir1. 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 R

educ

tion

in A

1C (

%)

Weight Gain (kg)

7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006

77

8

8 99

Intensive Insulin Therapy Robert E. Jones, MD, FACP, FACE Professor of Medicine University of Utah...

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