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Type 1 Diabetes Treatment Options

Type 1 Diabetes Treatment Options. Part 3. Stanley Schwartz Mark Stolar Emeritus, Univ of Pa. 30%. 50%. 55%. 60%. 70%. 70%. 50%. 45%. 40%. 30%. 9.3-10.2. >10.2. 8.5-9.2. 7.3-8.4. <7.3.

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Type 1 Diabetes Treatment Options

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

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

  3. The Basal/Bolus Insulin Concept • Basal insulin • Suppresses glucose production between mealsand 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. Rapid-Acting Insulin Analogs Provide Ideal Prandial Insulin Profile Breakfast Lunch Dinner Fast Analog Therapy Insulin Action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time 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. Basal/Bolus Treatment Program WithRapid- and Long-Acting Analogs Breakfast Lunch Dinner Fast Analogs Insulin Action Basal 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time 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 Please see accompanying prescribing information

  6. Basal Infusion The Insulin Pump as Adjunctive Therapy Breakfast Lunch Dinner Bolus Bolus Bolus Insulin Action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  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’

  8. Glucose, etc βcell α cell    No Insulin Glucagon 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) α cells β cells 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.

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

  10. Optimal insulin dose 700 GCG (55 pg/mL) GCG (52 pg/mL) Suboptimal insulin dose + leptin infusion 600 GCG (140 pg/mL) 500 400 Glucose, mg/dL 300 200 100 0 0 2 4 6 8 10 12 14 16 18 Time, day Correcting Hyperglucagonemia May Improve Glucose Variability: Evidence in Mice • Leptin correction of hyperglucagonemia decreased glucose variability • Decreased insulin dose prevented hypoglycemia • 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 GCG, glucagon Unger RH, et al. J Clin Invest. 2012;122(1):4-12.

  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. Insulin Meal Meal Meal Meal Amylin 20 30 n=6 healthy subjects 600 Without diabetes (n=27) 25 15 20 400 10 Plasma amylin (pM) Plasma amylin (pM) Plasma insulin (pM) Insulin-using Type 2(n=27) 15 200 5 Type 1(n=190) 10 0 0 5 -30 0 30 60 90 120 150 180 7 am Noon 5 pm Midnight Time after Sustacal meal (min) Time Amylin: Co-secreted With Insulin and Deficient in Diabetes • 37-amino acid peptide • Located almost entirely in β-cells • Cosecreted with insulin during meals • Receptor characterized in CNS Adapted from Koda JE, et al. Diabetes. 1995.

  13. Amylin * Glucagon Secretion Satiety * Gastric Emptying Digestion Glucose * In man Insulin Glucoregulatory Actions of Amylin

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