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The ROLE of GLUCAGON in DIABETES : An Update Pierre Lef èbvre

The ROLE of GLUCAGON in DIABETES : An Update Pierre Lef èbvre. Cairo, Egypt, September 2007. 1923. Murlin et al The discovery. 1942 Czyste Hospital Warsaw Ghetto. Studies on « Hunger’s disease » by Dr Emil Apfelbaum et al. 1949. Foà* et al Cross-circulation experiments

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The ROLE of GLUCAGON in DIABETES : An Update Pierre Lef èbvre

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  1. The ROLE of GLUCAGON in DIABETES :An Update Pierre Lefèbvre Cairo, Egypt, September 2007

  2. 1923 Murlin et al The discovery

  3. 1942Czyste Hospital Warsaw Ghetto Studies on « Hunger’s disease » by Dr Emil Apfelbaum et al

  4. 1949 Foà* et al Cross-circulation experiments *Only Author I know to have published a paper when in utero …

  5. Paradoxical hyperglycemia in the dog receiving PDV blood Insulin-induced hypoglycemia in the « donor » dog

  6. 1959-1960 Unger et al The first polypeptide radio-immunoassay

  7. Roger UNGER

  8. 1973

  9. Topics • Importance of glucagon for the maintenance of glucose homeostasis • The physiology of glucagon production and how glucagonexerts its effects • Abnormalities of glucagon secretion in patients with T2DM

  10. -Cells -Cells Insulin Glucagon – + + Glucose HGO Glucose uptake Pancreatic Islet Hormones Are Critical for Normal Glucose Tolerance HGO = hepatic glucose output Adapted from Unger RH. Metabolism. 1974;23:581–593

  11. – + Insulin* (plasma concentration) Glucagon* (plasma concentration) Glucose (plasma concentration) + – The Physiological Balance Between Insulin and Glucagon is Essential for Normal Metabolic Control *Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998:822–847

  12. = Glucose production Glucose utilization α-Cell Glucagon + 4 g/h Blood glucose4.5 mmol/L (81 mg/dL) 10 g/h 6 g/h Adapted from Unger RH. Diabetes. 1983;32:575–583 Glucagon is Important to Maintain Adequate FPG Levels Between Meals

  13. CHO Meal 120 Glucose mg% 100 80 120 80 Insulin μU/mL 40 0 120 110 Glucagon pg/mL 100 90 –60 0 60 120 180 240 Time (min) Normal Reciprocal Response of Insulin and Glucagon in Persons Without Diabetes Postprandial Insulin and Glucagon Responses in Persons Without Diabetes CHO = carbohydrate Adapted from Unger RH, et al. N Engl J Med. 1971;285:443–449

  14. Topics • Importance of glucagon for the maintenance of glucose homeostasis • The physiology of glucagon production and how glucagonexerts its effects • Abnormalities of glucagon secretion in patients with T2DM

  15. α-Cell Function is Regulated by Nutrient, Neural and Hormonal Influences Adapted from Dunning BE, et al. Diabetologia. 2005;48:1700–1713

  16. Glucagon + Glycogenolysis + Gluconeogenesis  Glucose - Glycolysis - Glycogenesis  HGP Glucagon Stimulation of Hepatocytes Leads to Increased Hepatic Glucose Production TCA = trichloroacetic acid Adapted from McMurry J, et al.Fundamentals of General, Organic, and Biological Chemistry. 4th ed.Upper Saddle River, NJ:Prentice Hall; 2006Jiang G, ZhangBB. Am JPhysiol Endocrinol Metab. 2003;284:E671-E678

  17. START INFUSION* N = 8† 150 75%  in HGP 100 Net Splanchnic Glucose Production (mg/min) 50 <.01 vs baseline <.01 <.01 <.01 <.01 <.01 <.01 <.01 –30 0 30 60 90 120 Time (min) Glucagon From α-Cells is Responsible for 75%of HGP HGP = hepatic glucose production *Somatostatin and insulin were delivered to induce selective glucagon deficiency †Healthy, non-obese men age 18–30 Adapted from Liljenquist JE, et al. J Clin Invest. 1977;39:369–374

  18. 350 – 300 – 250 – 200 – 150 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0 – 40 – 30 – 20 – 10 – 0 – | | | | | | | | | | | | | | | | | | 0 120 240 360 480 600 0 120 240 360 480 600 0 120 240 360 480 600 Minutes Minutes Minutes Changes in Glucagon/Insulin Ratio Regulate HGO and Glycogen Synthesis in Normal Physiology Glucagon/Insulin ratio* HGO (mg/kg.min)*† Liver Glycogen (mmol/L)* (n= 6) (n= 6) (n= 8) HGO = hepatic glucose output *All measurements made after a standard mixed meal in healthy volunteers ages 18–40 years †HGO completely suppressed after 30 minutes of meal intake Adapted from Taylor R, et al. J Clin Invest. 1996;97:126–132

  19. Topics • Importance of glucagon for the maintenance of glucose homeostasis • The physiology of glucagon production and how glucagonexerts its effects • Abnormalities of glucagon secretion in patients with T2DM

  20. Normal T2DM β-Cells(insulin) Amyloid plaque α-Cells (glucagon) • Disorganised and misshapen • Marked reduction in β-cell number • Amyloid plaques Pancreatic Islet Morphology: Structural Defects are Evident in T2DM T2DM = type 2 diabetes mellitus Adapted from Rhodes CJ. Science. 2005; 307:380–384

  21. T2DM pancreatic islet Fewer -cells -cell hypertrophy Insufficient insulin Excess glucagon – + Glucose ↑ Less effective glucose uptake ↑ HGO Islet Dysfunction Leads to Hyperglycaemiain T2DM HGO = hepatic glucose output Adapted from Unger RH. Metabolism. 1974;23:581–593

  22. CHO meal 400 300 NGT mg/dL T2DM 200 Glucose 100 0 150 100 μU/mL NGT Insulin 50 T2DM 0 150 Glucagon 125 pg/mL NGT 100 T2DM 75 –60 0 60 120 180 240 Time (min) In T2DM, Insufficient Insulin and Elevated Glucagon Secretion Result in Hyperglycaemia Adapted from Müller WA, et al.N Engl J Med. 1970;283:109–115

  23. 2.8 Diagnosis 2.4 2.0 Glucose Clearance (mL/kg•min) Impairedinsulin-mediated glucose disposal 1.6 1.2 0.8 50 100 150 200 250 300 4.5 Excessive glucagon-mediated glucose output 4.0 3.5 Glycogenolysis andGluconeogenesis(mg/kg•min) 3.0 2.5 2.0 1.5 1.0 50 100 150 200 250 300 FPG (mg/dL) Decreased Glucose Disposal and Increased HGP Contribute to Increased FPG in T2DM HGP = hepatic glucose production; FPG = fasting plasma glucose; T2DM = type 2 diabetes mellitus Adapted from DeFronzo RA. Diabetes. 1988;37:667–687

  24. NGT (n= 12) Meal T2DM (n= 18) Endogenous Glucose(µmol/min/kg) 18 14 10 6 -30 -15 0 30 60 90 120 150 180 210 240 270 300 2 Time (minutes) Suppression of Endogenous Glucose Production is Impaired in T2DM HGO = hepatic glucose output Adapted from Kelley D, et al. Metabolism. 1994;43:1549–1557

  25. 180 - 150 - 120 - 90 - 60 - 30 - NGT* (n = 8) T2DM (n = 8) AGRarg (pg/mL) PG50 0 100 200 300 400 500 600 700 Plasma Glucose Level (mg/dL) α-Cell Sensitivity to Glucose is Reduced in T2DM AGRarg= mean acute glucagon response to arginine from 2 to 5 min; PG50 = plasma glucose level required for half-maximal suppression of AGRarg T2DM = type 2 diabetes mellitus; *Healthy men ages 18–29 Adapted from Ward WK, et al. J Clin Invest. 1984;74:1318–1328. Dunning B, et al. Diabetologia. 2005;48:1700–1713

  26. Glucagon Glycogenolysis§ Glucose (n= 9) Non-suppressed glucagon Suppressed glucagon 50-g glucose‡ 50-g glucose 50-g glucose 4,500 ↓ ↓ ↓ 200 12 150 10 † † † 3,000 † ‡ dpm/kg/min ‡ 100 Glucagon (ng/L) Glucose (mmol/L) 8 ‡ ‡ 1,500 50 6 0 0 4 -60 0 60 120 180 240 300 360 -60 0 60 120 180 240 300 360 360 0 60 120 180 240 300 Time (min) Time (min) Time (min) In Patients with T2DM, Suppression of Glucagon Reduces Glycogenolysis and Plasma Glucose Levels †P <0.0001 between groups; ‡P <0.001between groups §As assessed by [14C] glucose appearance Protocol: somatostatin and insulin delivered to mimic glucagon deficiency, then glucagon infused to simulate a non-suppressed day,or delayed by 2 hours to create transient glucagon deficiency (suppressed day) Adapted from Shah P, et al. J Clin Endocrinol Metab. 2000;85:4053–4059

  27. Effect of a glucagon monoclonal antibody on glucose excursion during an OGTT In ob/ob mice. Data from Sorensen et al , Diabetes 2006, 55: 2843-2848 m

  28. Hyperglucagonemia is a feature of all forms of diabetes • « Dual A- and B-cell abnormality » ? • A-cell insulin resistance ? • Hyperglycemia-induced desensitization of the A-cell (Glucotoxicity ? )

  29. An alternative hypothesis* • -Insulin and glucagon are secreted in a pulsatile manner • -Normal intra-islet insulin pulsatility helps avoiding excessive glucagon release • -Normal insulin pulsatility is lost in diabetes • Thus, loss of normal intra-islet insulin pulsatility may be involved in the hyperglucagonemia of diabetes • *Lefèbvre, Paolisso and Scheen 1991

  30. Lelio ORCI

  31. Pulsatile insulin and glucagon-induced glucagon release* • Nine Type 1 diabetic patients • Very small insulin infusion given either continuously (circulating insulin levels ~15 µU/ml) or same total amount of insulin given in 13 min pulses and both compared to saline infusion • No significant effect on blood glucose • After 52 minutes, 5gm iv arginine pulse and evaluation of integrated glucagon response • *Paolisso et al , JCEM1988,66: 1220-26

  32. New support for the intra-islet insulin hypothesis • MEIER JJ, KJEMS LL, VELDHUIS JD , LEFEBVRE PJ and BUTLER PC : • Postprandial Suppression of Glucagon Secretion Depends on Intact Pulsatile Insulin Secretion : Further Evidence for the Intraislet Insulin Hypothesis* • *Diabetes , 55:1051-1056,2006

  33. Glucagon pulses in the basal state prior to alloxan in a representative pig

  34. GLUCAGON Pulse mass, height and interval in the fasting state and after a meal studied both before and after alloxan in 7 pigs* *Meier et al , 2005 submitted

  35. Mean cross-correlogramms between insulin and glucagon concentrations time series in 7 pigs studied over 90 min after a test meal, each prior and after alloxan treatment. The relationship between insulin and glucagon levels is significant before but disappears after alloxan

  36. « Forward » and « reverse » cross-AsPen analyses imply that, in the post-prandial state, pulsatile insulin secretion directly suppresses glucagon secretion, but that this association is lost after a ~60% reduction in beta cell mass

  37. In conclusion • It is confirmed that glucagon is secreted in distinct pulses both in the fasting state and after a meal • In healthy minipigs, suppression of glucagon secretion after a meal is likely accomplished, at least in part, by increased insulin secretion • This action of insulin is lost in the minipig alloxan model of Type 2 diabetes mellitus in which post-prandial insulin secretion is impaired as a consequence of an ~60% decrease in beta-cell mass • We conclude that post-prandial hyperglucagonemia in diabetes is likely due ,at least in part, to impaired insulin secretion leading to a loss of intra-islet driven suppression of glucagon secretion

  38. Potential Clinical Consequence:The best way to normalize the hyperglucagonemia of diabetesmay be to restore normal insulinsecretion , including pulsatility …Increase in amplitude of insulin pulses, without changes infrequency,reported by a 6wk GLP1 infusion in 5 old patients with T2DM by Meneilly et alJCEM, 2005, 90: 6251-56

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