Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis
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.
- 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.
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
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
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
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
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
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.
Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes
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
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
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.
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)
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
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?
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.
The Development and Progression of Type 2 Diabetes
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.
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).