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

2. 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

3. Intensive Insulin Therapy

4. Insulin Effect B D LHS Bolus insulin Basal 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

5. 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

6. Basic Insulin Regimen: Split- Mixed Regimen or Premix Regular NPH BDLHSB Endogenous insulin

7. 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

8. The Mathematics

9. 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)

10. 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)

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

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

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

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

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

16. 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)

17. Simple Equations TDD = Basal + Bolus (50:50) CF = 1700/TDD CIR = 0.33 * CF UDPRs, 2008 IHC Diabetes Care Model, 2010

18. Comparisons ParameterSimpleAIM400/500 EqnResultEqnResultEqnResult BasalTDD*0.515TDD*0.4714.1TDD*0.515 CF1700/TDD56.71700/TDD56.71700/TDD56.7 CIRCF*0.331:18.72.8*BWlb/ TDD 1:14441/TDD1:14.7 25 year old 150 lb woman who requires 30 U/day

19. Comparisons ParameterSimpleAIM400/500 EqnResultEqnResultEqnResult BasalTDD*0.525TDD*0.4723.5TDD*0.525 CF1700/TDD341700/TDD341700/TDD34 CIRCF*0.331:11.22.8*BWlb/ TDD 1:8.4441/TDD1:8.8 25 year old 150 lb woman who requires 50 U/day

20. Comparisons 45 year old 200 lb man who requires 110 U/day ParameterSimpleAIM400/500 EqnResultEqnResultEqnResult BasalTDD*0.555TDD*0.4751.7TDD*0.555 CF1700/TDD151700/TDD151700/TDD15 CIRCF*0.331:5.02.8*BWlb/ TDD 1:5.1441/TDD1:4.0

21. 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

22. Insulin Kinetics

23. Euglycemic Hyperinsulinemic Clamp Glucose (mg/dL) 110 70 50 90 80 40 0 Insulin (  U/mL) 48 36 24 12 Glucose Infusion Rate (  mol/min  kg) 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/m 2. 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.

24. Analog Insulin Profiles Rosenstock J. Clin Cornerstone. 2001;4:50-61. 0 2468 10 12141618202224 Plasma Insulin Levels Time (hr) NPH (10–20 hr) Regular (6–10 hr) Glargine (~24 hr) Aspart, Lispro, Glulisine (4 – 5 hr) Detemir ~18-24hr

25. What Can Influence Insulin Kinetics?

26. 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.

27. 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.

28. 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

29. 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) -60060120180240300360420480540 Aspart 1,2 Plasma Insulin Levels Effect of Premixing on Rapid- Acting Analog Properties T max 49-53 min 70/30 NovoLog Mix 3 T max 2.4 hours

30. Glucose Infusion Rate mg/dl 0.3 U/Kg NPH s.c. Plasma Glucose 90 80 70 5.0 4.5 4.0 mmol/l Lepore M. et al., unpublished data 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 01234567890123456789 Time (hours) µmol/Kg/min mg/Kg/min PEN UP PEN DOWN MIX Effect of Insulin Suspensions on GIR

31. What Else Can Influence Insulin Kinetics? Site of injection Local blood flow –Exercise –Obesity Inherent variability Absentmindedness Effect of food

32. Effect of Food Mondo Mama’s Pizza Or Think Outside the Box... Mondo Mama’s Pizza

33. Effect of Food Mondo Mama’s Pizza Or Think Outside the Box... DUAL WAVE BOLUS Mondo Mama’s Pizza

34. Effect of Food Mondo Mama’s Pizza Or Think Outside the Box... RAA + RHI (50/50 Mix) Mondo Mama’s Pizza

35. 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?

36. Cases

37. 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; CO 2 19 mEq/L What does he have and how would you treat him?

38. 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

39. 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?

40. B D L HS Insulin Effect Metformin Basal Insulin Secretogogue Case 2

41. 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.

43. Florentine Arch

44. Hypoglycemia Severe insulin reactions per 100 patient-yr 7.8 3 2.3 110 62 020406080100120 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

45. 0.5 0 1 1.5 2 Weight v Delta A 1C Studies with Type 2 Diabetes 1234 Glargine NPH 1 1 4 2 2 3 3 4 2 6 5 6 5 Detemir 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 Reduction in A 1C (%) Weight Gain (kg) 7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006 7 7 8 8 9 9

46. Insulin Self Association Sites