1. Type 1 Diabetes Treatment Options Stanley Schwartz Mark Stolar Emeritus, Univ of Pa Part 3

2. Postprandial Glucose Contribution to A1C % Contribution A1C Range (%) 0 20 40 60 80 100 FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) >10.2 70% 30% 9.3-10.2 60% 40% 8.5-9.2 55% 45% 7.3-8.4 50% <7.3 30% 70% Data from Monnier L, et al. Diabetes Care 2003; 26:881-885

3. The Basal/Bolus Insulin Concept Basal insulin – Suppresses glucose production between meals and overnight – Nearly constant levels – ~50% of daily needs Bolus insulin (mealtime or prandial) – Limits hyperglycemia after meals – Immediate rise and sharp peak at 1 hr – ~10% to 20% of daily requirement at each meal Ideally, for insulin replacement therapy, each component should come from a different insulin with specific profile Rosenstock J. Clin Cornerstone. 2001;4:50

4. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Insulin Action Rapid-Acting Insulin Analogs Provide Ideal Prandial Insulin Profile Fast Analog Therapy Adapted with permission from Leahy JL. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker Inc.; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

5. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal Basal/Bolus Treatment Program With Rapid- and Long-Acting Analogs Insulin Action Adapted with permission from Leahy JL. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker Inc.; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342 Fast Analogs Please see accompanying prescribing information

6. The Insulin Pump as Adjunctive Therapy 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 Time Bolus Basal Infusion Insulin Action 12:008:00

7. β-Cell (Islet Cell) Classification Model- Implications for Therapy: Targets for Adjunctive Therapies Direct Effect on β-Cells On #1-3 of ‘ Egregious Eleven ’ 1β-CELLIncretin 2 α-Cell Glucagon Incretin, Pramlintide 3↓INCRETIN EFFECTIncretin 4 Egregious Eleven Defect Intervention / Therapy

8. Disrupted Insulin and Glucagon Regulation: Central Role in Diabetes Pathophysiology Hyperglucagonemia is a characteristic of T1DM and T2DM Data suggest a central role for glucagon dysregulation in diabetes pathophysiology – Without paracrine intraislet insulin signals from juxtaposed β cells (image), α cells hypersecrete glucagon (diagram) – Hyperglucagonemia can account for abnormalities associated with lack of insulin (eg, increased ketogenesis) Cryer P. Endocrinology. 2012;153:1039-1048. Unger R, et al. J Clin Invest. 2012;122:4-12. Bosco D, et al. Diabetes. 2010;59:1202-1210.  Glucose, etc  GlucagonNo  Insulin α cell β cell  α cells β cells

9. Unger RH, et al. J Clin Invest. 2012;122(1):4-12. Type 1 DM Glucagon Is Central to Hyperglycemia in Type 1 Diabetes: ie Exogenous Insulin Doesn ’ t Suppress Glucagon Insufficient

10. GCG (140 pg/mL) Correcting Hyperglucagonemia May Improve Glucose Variability: Evidence in Mice Leptin correction of hyperglucagonemia decreased glucose variability Decreased insulin dose prevented hypoglycemia Unger RH, et al. J Clin Invest. 2012;122(1):4- 12. GCG, glucagon NOD mice (T1DM model) Optimal insulin dose: 0.2 U twice daily Suboptimal insulin dose: 0.02 U twice daily Leptin infusion to suppress glucagon 700 600 500 400 200 100 026818 Time, day Glucose, mg/dL 0 300 161412104 GCG (52 pg/mL) GCG (55 pg/mL) Optimal insulin dose Suboptimal insulin dose + leptin infusion

11. Addressing the alpha cell in type 1 Diabetes Glucagon dysregulation is a key contributor to increased risk of hypoglycemia and hyperglycemia in T1DM and T2DM Increased risk of hypoglycemia can be mitigated by educating patients regarding signs, symptoms, and treatment of hypoglycemia and can be treated with exogenous glucagon Approaches to correct hyperglucagonemia may improve glycemic control in patients with T1DM At present only pramlintide is approved to treat the glucagon defect in Type 1 Diabetes

12. ● 37-amino acid peptide ● Located almost entirely in  -cells ● Cosecreted with insulin during meals ● Receptor characterized in CNS Adapted from Koda JE, et al. Diabetes. 1995. Amylin: Co-secreted With Insulin and Deficient in Diabetes

13. Glucoregulatory Actions of Amylin