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Intensive Insulin Therapy. Robert E. Jones, MD, FACP, FACE Professor of Medicine University of Utah School of Medicine. Objectives. Define intensive insulin therapy Explore the basis of insulin therapeutics:

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Intensive insulin therapy l.jpg

Intensive Insulin Therapy

Robert E. Jones, MD, FACP, FACE

Professor of Medicine

University of Utah School of Medicine


Objectives l.jpg
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



Physiologic insulin therapy l.jpg
Physiologic Insulin Therapy

Bolus insulin

Basal insulin

Insulin Effect

D

B

L

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 l.jpg
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 l.jpg

Endogenous insulin

Regular

NPH

B

L

D

HS

B

Basic Insulin Regimen: Split-Mixed Regimen or Premix


Basal vs bolus insulin l.jpg

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

Basal vs Bolus Insulin



The systems l.jpg
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 l.jpg
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 l.jpg
Regression Models

Davidson PC et al. Endocr Pract 14:1095-1101 (2008)


Regression models12 l.jpg
Regression Models

Davidson PC et al. Endocr Pract 14:1095-1101 (2008)


Regression models13 l.jpg
Regression Models

Davidson PC et al. Endocr Pract 14:1095-1101 (2008)


Regression models14 l.jpg
Regression Models

Davidson PC et al. Endocr Pract 14:1095-1101 (2008)


Regression models15 l.jpg
Regression Models

Davidson PC et al. Endocr Pract 14:1095-1101 (2008)


Aim equations l.jpg
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 l.jpg
Simple Equations

  • TDD = Basal + Bolus (50:50)

  • CF = 1700/TDD

  • CIR = 0.33 * CF

UDPRs, 2008

IHC Diabetes Care Model, 2010


Comparisons l.jpg
Comparisons

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


Comparisons19 l.jpg
Comparisons

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


Comparisons20 l.jpg
Comparisons

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


Comparison conclusions l.jpg
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



Euglycemic hyperinsulinemic clamp l.jpg

110

90

70

Glucose (mg/dL)

50

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.

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.

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.

80

48

36

Glucose Infusion Rate (mol/minkg)

40

24

Insulin (U/mL)

12

0

0

60

80

Time (min)


Analog insulin profiles l.jpg

Aspart, Lispro, Glulisine (4–5 hr)

Glargine (~24 hr)

Analog Insulin Profiles

Regular (6–10 hr)

NPH (10–20 hr)

Plasma Insulin Levels

Detemir ~18-24hr

2

4

6

8

12

14

16

18

20

22

24

0

10

Time (hr)

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



Effect of dose lispro pk l.jpg
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 l.jpg
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 l.jpg
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 28:1107-1112 (2005).


Effect of premixing on rapid acting analog properties l.jpg

Aspart 1,2

70/30 NovoLog Mix 3

-60

0

60

120

180

240

300

360

420

480

540

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 2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-201 3. Novo Nordisk, data on file


Effect of insulin suspensions on gir l.jpg

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

PEN DOWN

MIX

mg/Kg/min

µmol/Kg/min

PEN UP

0 1 2 3 4 5 6 7 8 9

Time (hours)

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


What else can influence insulin kinetics l.jpg
What Else Can Influence Insulin Kinetics?

  • Site of injection

  • Local blood flow

    • Exercise

    • Obesity

  • Inherent variability

  • Absentmindedness

  • Effect of food


Effect of food l.jpg
Effect of Food

Or Think Outside the Box...

Mondo Mama’s Pizza

Mondo Mama’s Pizza


Effect of food33 l.jpg
Effect of Food

Or Think Outside the Box...

DUAL WAVE BOLUS

Mondo Mama’s Pizza

Mondo Mama’s Pizza


Effect of food34 l.jpg
Effect of Food

Or Think Outside the Box...

Mondo Mama’s Pizza

Mondo Mama’s Pizza

RAA + RHI (50/50 Mix)


Difficult questions that were not asked l.jpg
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 l.jpg
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 138 l.jpg
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 l.jpg
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 240 l.jpg
Case 2

Metformin

Basal Insulin

Secretogogue

Insulin Effect

HS

B

L

D


Case 3 l.jpg
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.



Hypoglycemia l.jpg

Severe insulin reactions per 100 patient-yr

0

20

40

60

80

100

120

62

DCCT

Type 1 diabetes

110

SDIS

2.3

UKPDS

Type 2 diabetes

3

VA CSDM

7.8

VA IIIP

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

Hypoglycemia


Weight v delta a 1c studies with type 2 diabetes l.jpg

8

7

Glargine

NPH

Weight v Delta A1CStudies with Type 2 Diabetes

2

Detemir

7

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

3

3

1.5

9

9

4

Reduction in A1C (%)

1

8

4

1

1

2

5

5

0.5

2

2

6

6

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

0

1

2

3

4

Weight Gain (kg)


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