2. Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis

3. Learning Objectives After participating in this educational activity, you will be able to: Describe the role of islet cells ( and β) in maintaining normal glucose homeostasis. Understand disturbances in β-cell function, glucagon secretion, and hepatic glucose production in type 2 diabetes. Describe the progressive nature of β-cell dysfunction and its role in the pathogenesis of type 2 diabetes.

4. - and -Cells in the Pancreas of Normal Individuals Produce glucagon 1 Produce insulin and amylin 3 Glucagon released in response to low blood glucose levels 1 Insulin released in response to elevated blood glucose levels 1 Comprise about 15% of the endocrine mass of the pancreas 1 Comprise about 70%–80% of the endocrine mass of the pancreas 1,2 Located in the periphery of the islet 1 Located in the central portion of the islet 1,2 -Cells 1. Cleaver O et al. In: Joslins Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39. 2. Rhodes CJ. Science. 2005;307:380–384. 3. Kahn SE et al. Diabetes. 1998;47:640–645.

5. N=11. Adapted with permission from Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725. Insulin Increases and Glucagon Falls in Response to Meals in Normal Subjects Minutes After Meal Ingestion –60060120180240300360 180 126 72 mg/dL ( - ) Glucose 400 200 0 pM ( - ) Insulin 105 75 45 ng/L ( - ) Glucagon

6. The Normal β-Cell Insulin Response to Intravenous (IV) Glucose Is Biphasic 2nd phase N=17 subjects. Hyperglycemic clamp technique was used. Adapted with permission from Pratley RE et al. Diabetologia. 2001;44:929–945. © Springer-Verlag, 2001. 0 100 200 300 400 500 020406080100120 Time, min Plasma Insulin, pmol/L 1st phase

7. Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects Men Women 2,000 1,500 1,000 500 0 0510152025 95th 50th 5th AIRglucose=first-phase insulin response. Insulin response examined following intravenous administration of glucose. N=93 apparently healthy subjects aged <45 yrs. Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers; 2001;109–131. Figure 2. With kind permission from Springer Science and Business Media. AIRglucose, pM Insulin Sensitivity Index, S i x 10 –5 min –1 /pM

8. Compensatory β-Cell Insulin Secretion With Increasing Insulin Resistance 95th 50th 5th In subjects without diabetes, insulin secretion is modulated by the prevailing degree of insulin sensitivity. For glucose tolerance to remain constant when insulin sensitivity varies, a proportionate and reciprocal alteration in insulin output has to occur. AIRmax=measure of the β-cell secretory capacity. β-cell secretory capacity to nonglucose secretagogue arginine was used to characterize the relation between insulin release and glucose level. N=43 subjects with varying degrees of obesity, aged <45 years, fasting plasma glucose <115.2 mg/dL. Adapted from Kahn SE et al. Diabetes. 1993;42:1663–1672. Modified with permission from The American Diabetes Association. Copyright © 1993 American Diabetes Association. 0 1,000 2,000 3,000 4,000 5,000 0510152025 AIRmax, pM Men Women Insulin Sensitivity Index, S i x 10 –5 min –1 /pM

9. Net Hepatic Glucose Output, µmoL kg –1 min –1 Hepatic Sinusoidal Insulin, pmol/L Net Hepatic Glucose Output, µmoL kg –1 min –1 Hepatic Sinusoidal Glucagon, ng/L Experiment carried out in overnight fasted conscious dogs. Adapted from Cherrington AD. Copyright © 1999 American Diabetes Association. From Diabetes, 1999;48:1198– 1214. Reprinted with permission from The American Diabetes Association. Insulin vs Net Hepatic Glucose Output Glucagon vs Net Hepatic Glucose Output Fixed basal glucagon level 0 20 40 60 0240480720 0 20 40 60 0200400600 Hepatic Glucose Production in Dogs Is Regulated by Insulin and Glucagon Fixed basal insulin level

10. Insulin and Glucagon Regulate Normal Glucose Homeostasis Glucose output Glucose uptake Glucagon (α-cell) Insulin (β-cell) Pancreas LiverMuscle Porte D Jr et al. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Blood glucose

11. Role of Selected Organs in Normal Glucose Homeostasis Glucagon Fat Plasma Glucose Pancreas Liver α β Adapted with permission from Kahn CR, Saltiel AR. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Brain Muscle Insulin Insulin-dependent glucose uptake Insulin Insulin-independent glucose uptake

12. Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects Insulin from β-cells Blood glucose homeostasis Ingestion of food Pancreas -cells Glucagon from α-cells Glucose production by liver Glucose uptake by adipose and muscle tissue Release of gut hormones GI tract Glucose dependent

13. Summary of the Role of the Pancreatic Islet in Normal Glucose Homeostasis Pancreatic α- and β-cells play several key roles in maintaining normal glucose homeostasis by regulating insulin and glucagon. 1 The normal β-cell insulin response is biphasic, with a first (early) phase and a second (late) phase. 2 In response to glucose loading, insulin levels increase and glucagon levels fall to maintain normal glucose homeostasis. 3 To maintain normal glucose homeostasis, any change in insulin sensitivity is balanced by a reciprocal and proportionate change in β-cell function. 4 1. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. 2. Pratley RE, Weyer C. Diabetologia. 2001;44:929–945. 3. Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725. 4. Kahn SE et al. Diabetes. 1993;42:1663–1672.

14. Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes

15. Glucose output Glucose uptake Glucagon (α-cell) Insulin (β-cell) Pancreas Liver Hyperglycemia Muscle Islet cell dysfunction 1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance 1,2 * *Reduced effect of insulin indicating insulin resistance

16. First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes Normal Type 2 Diabetes n=9 normal; n=9 type 2 diabetes. Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588. With permission from Excerpta Medica, Inc. 0 20 40 60 80 100 120 –300306090120 Time, min 0 20 40 60 80 100 120 –300306090120 Time, min Plasma Insulin, µU/mL

17. Some Abnormalities of β-Cell Function in Type 2 Diabetes Disrupted pulsatile insulin response 1 proinsulin/insulin ratio 1 β-cell responsiveness to glucose 2,3 insulin production 4 – insulin – insulin granules β-Cell dysfunction 1. Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46. 2. Buse JB et al. In: Larsen PR et al. Williams Textbook of Endocrinology. 10th ed. Saunders; 2003;1427–1483. 3. Ward WK et al. J Clin Invest. 1984;74:1318–1328. 4. Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541.

18. Patients With Type 2 Diabetes Have Decreased β-Cell Responsiveness to Glucose n=11 control; n=11 type 2 diabetes. ISR=insulin secretory rate; BMI=body mass index. Adapted with permission from Byrne MM et al. Am J Physiol Endocrinol Metab. 1996;270:E572–E579. Type 2 diabetes Control 0 5 10 15 20 25 30 50100150200250300 Glucose, mg/dL ISR/BMI, pmol x m 2 /(min x kg)

19. N=277 Pima Indians; NGT=normal glucose tolerance; IGT=impaired glucose tolerance; T2DM=type 2 diabetes; EMBS=estimated metabolic body size. Changes in β-cell function, measured as acute insulin response to glucose (AIRglucose) relative to changes in insulin sensitivity, measured by clamp technique at a low insulin concentration (M-low). Adapted with permission from Weyer C et al. J Clin Invest. 1999;104;787–794. AIRglucose, μU/mL M-Low, mg/kg EMBS/min 0 100 200 300 400 500 012345 T2DM IGT NGT Nonprogressors Progressors The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes

20. Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes –60060120180240 360 330 300 270 240 110 80 140 130 120 110 100 90 120 90 60 30 0 Glucose, mg % Insulin, μ/mL Glucagon, μμ/mL Meal (minutes) Type 2 diabetes Normal patients n=12 normal; n=12 type 2 diabetes. Adapted with permission in 2005 from Müller WA et al. N Engl J Med. 1970;283:109–115. Copyright © 1970 Massachusetts Medical Society. All rights reserved.

21. P<0.001 Fasting Fasting and Postprandial Glucagon Levels Are Elevated in Patients With Impaired Glucose Intolerance and Type 2 Diabetes P<0.001 Postprandial NGT=normal glucose tolerance, n=33; IGT=impaired glucose tolerance, n=15; T2DM=type 2 diabetes mellitus, n=54. Toft-Nielson M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723. Fasting Plasma Glucagon, pmol/LPostprandial Glucagon at 240 min, pmol/L

22. Lack of Suppression of Glucagon Causes Postprandial Hyperglycemia in Type 2 Diabetes * 72 108 144 180 216 –60060120180240300360 Time, min Glucose, mg/dL Nonsuppressed glucagon Suppressed glucagon *P<0.001. N=9 (7 men, 2 women). Reprinted with permission from Shah P et al. J Clin Endocrinol Metab. 2000;85:4053–4059. Copyright © 2000, The Endocrine Society.

23. The abnormalities in β-cell function typically include: A.Decreased insulin production and increased proinsulin/insulin ratio B.Abnormal pulsatile insulin response C.Decreased β-cell responsiveness to glucose D.All of the above What Are the Abnormalities in β-Cell Function Seen in Type 2 Diabetes?

24. Summary of Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes Islet cell dysfunction and insulin resistance play important roles in the pathophysiology of type 2 diabetes. 1 In type 2 diabetes: –First-phase insulin response by β-cells is lost. 2 –There is abnormal β-cell function and decreased β-cell responsiveness to glucose. 3 –Endogenous glucose production is elevated. 4 –Fasting and postprandial glucagon secretion are elevated. 4,5 1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Ward WK et al. Diabetes Care. 1984;7:491–502. 3. Kahn SE. Diabetologia. 2003;46:3–19. 4. Basu A et al. J Invest Med. 2004;52:366–374. 5. Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

25. The Development and Progression of Type 2 Diabetes

26. Patients at High Risk of Type 2 Diabetes Have Inadequate β-Cell Compensation for Degree of Insulin Resistance Type 2 diabetes Older subjects IGT AIRglucose, pmol/L Insulin Sensitivity Index, S i x 10 –5 min –1 /pmol/L 75th 50th 25th 5th Relatives of type 2 diabetes IGT=Impaired glucose tolerance, n=21; type 2 diabetes, n=10; older subjects, n=13; relatives, n=14. Percentile lines based on data from 93 healthy subjects. AIRglucose=first-phase insulin response. Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers; 2001;109–131. Figure 3. With kind permission from Springer Science and Business Media.

27. Inadequate Insulin Secretion and Insulin Action Occur Early in the Development of Type 2 Diabetes AIRglucose=acute insulin response; M-high=maximally insulin-stimulated glucose disposal. *P<0.05; **P<0.01. Adapted with permission from Weyer C et al. J Clin Invest. 1999;104:787–794. 0 50 250 NGT AIRglucose, µ/mL 150 100 200 IGTT2DM Overall Time Effect P<0.0001 NGT M-High, mg/kg EMBS/min IGTT2DM 300 0 2 10 6 4 8 12 Overall Time Effect P<0.0001 * ** Longitudinal study over 5.1 ± 1.4 years; N=17 Pima Indians in whom glucose tolerance deteriorated from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes (T2DM).

28. 0 0 40 60 80 HOMA % B 20 246 Years From Diagnosis 0 0 40 60 HOMA % S 20 246 β-Cell FunctionInsulin Sensitivity HOMA=Homeostasis Model Assessment; HOMA % B=β-cell function; HOMA % S=Insulin sensitivity. N=432. 10-year follow-up of the Belfast Diet Study. Data from Group 2 shown: newly diagnosed T2DM subjects who required additional treatment (due to secondary failure to diet therapy) at 5–7 years. Reproduced with permission from Levy J et al. Diabet Med. 1998;15:290–296. © 1998 Blackwell Publishing. -Cell Function Declines After Diagnosis, Whereas Insulin Sensitivity Remains Relatively Stable Years From Diagnosis

29. Years A1C, % Diet/conv Rx (n=297) Metformin (n=251) SU/intensive (n=695) Years Progressive Impairment of -Cell Function and Deterioration of Glycemic Control in Type 2 Diabetes -Cell Function Declines Over Time -Cell function, % β Diet/conv Rx (n=376) Metformin (n=159) SU/intensive (n=511) 012345 100 75 50 25 0 6 A1C Increases Over Time 012345 10 9 8 7 6 5 6 Diet/conv Rx=conventional therapy (diet alone); UKPDS=United Kingdom Prospective Diabetes Study; SU/intensive=sulfonylurea or insulin. N=4,209 newly diagnosed patients with type 2 diabetes. Reprinted from UK Prospective Diabetes Study Group 16. Copyright © 1995 American Diabetes Association. From Diabetes. 1995;44:1249–1258. Reprinted with permission from The American Diabetes Association.

30. What Are Some Determinants of -Cell Mass? Some determinants of -cell mass include: A.Cell proliferation rate B.Rate of cell death (apoptosis) C.Regeneration of β-cells (neogenesis) D.All

31. Some β-Cell Abnormalities in Type 2 Diabetes -cell mass 1,2 -cell apoptosis 1 Impaired β-cell proliferation 2,3 Impaired β-cell neogenesis 2,3 β-Cell abnormalities 1. Butler AE et al. Diabetes. 2003;52:102–110. 2. Donath MY, Halban PA. Diabetologia. 2004;47:581–589. 3. Rhodes CJ. Science. 2005;307:380–384.

32. Inside the Islet: Exploring Issues in Type 2 Diabetes In summary: The pathophysiology of type 2 diabetes includes islet cell dysfunction, insulin resistance, and increased hepatic glucose output. 1–3 Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin. 1 Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time. 1 1. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. 2. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 3. Del Prato S, Marchetti P. Diabetes Technol Ther. 2004;6:719–731. © 2006 Merck & Co., Inc. All rights reserved. 20551162(1)-01/06-JAN.