Presentation on theme: "Type 2 Diabetes: Pathophysiology and Opportunities for Treatment"— Presentation transcript:
1Type 2 Diabetes: Pathophysiology and Opportunities for Treatment Tyler Aguinaldo, MDDirector, Center for Diabetes & MetabolismSanta Clara Valley Medical CenterApril 16, 2009
2Objectives Review epidemiology of diabetes and pre-diabetes. Distinguish diabetes type 1 and type 2Describe the role of pancreatic islet cells ( and β) in maintaining normal glucose homeostasis.Understand disturbances in insulin resistance, β-cell function, glucagon secretion, hepatic glucose production and incretin hormones in type 2 diabetes.Summarize treatment options in type 2 diabetes.
3Number (in Millions) and Percent of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, U.S., 1980–2006
4National Diabetes Statistics, 2007 Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007:Total: 23.6 million people — 7.8 percent of the population — have diabetes.Diagnosed: 17.9 million peopleUndiagnosed: 5.7 million peoplePrevalence of Impaired Fasting Glucose in People Aged 20 Years or Older, United States, 2007In 2003 to 2006, 25.9 percent of U.S. adults aged 20 years or older had IFG —35.4 percent of adults aged 60 years or older, yields an estimated 57 million American adults aged 20 years or older with IFG
6The global diabetes epidemic 2000―2010 and beyond: prevalence of diabetes 26.584.514.232.9132.317.5+24%+57%+23%URGENT NEED FOR ACTION9.4There is an urgent need to treat and prevent diabetes mellitus as the prevalence of the disease continues to rise globally.Estimates predict an increase from 151 million in 2000 to 220 million sufferers by 2010.Wild S, et al. Diabetes Care 2004;27:1047―53.Zimmet P, et al. Nature 2001;414:782―220.127.116.11+50%22.51.0+44%1.32000: 151 million2010: 220 million + ~50%2025: 300 million + ~100%2030: 366 million + ~145%+33%Wild S, et al. Diabetes Care 2004;27:1047―53.Adapted from Zimmet P, et al. Nature 2001;414:782―7.
712.6M Treated With Oral Agents or Insulin NHANES: Glycemic Control in the U.S.20.8M Patients12.6M Treated With Oral Agents or InsulinYet Average A1CIs IncreasingNHANES1999–20006.2M Undiagnosed7.962%2M D&EA1C >7%12.6M Rx TreatedOf the 20.8 million people with diabetes in the United States, 6.2 million remain undiagnosed, while 12.6 million people are being treated with oral agents or with insulin.1According to the National Health and Nutrition Examination Survey (NHANES IV) , only 38% of treated diabetics achieved the target HbA1C (A1C) goal of < 7.0%.2 Although this figure did not change significantly from that reported in NHANES III (which encompassed the years 1988 to 1994), there was a 0.2% increase in the average A1C level from NHANES III to NHANES IV.Thus, despite the availability of numerous treatments for diabetes, glycemic control is worsening.1. National Diabetes Fact Sheet, Available at: Accessed December 2005.2. NHANES IV. Available at:NHANES1988–19947.738%A1C <7%AACE A1C Goal = 6.5%ADA A1C Goal = <7%CDC 2005, NHANES 1999–2002
9Two Main Classes of Diabetes Mellitus Type 1 Diabetes:Insulin deficiency (usually auto-immune)Accounts for 5-10% of total diabetesType 2 Diabetes:Multi-factorial:Insulin resistanceRelative insulin deficiencyDysregulation of glucagonAbnormalities in incretin hormonesAccounts for 90-95% of total diabetesAssociated with “Metabolic Syndrome”
11The Normal Pancreatic Islet “An understanding of the normal physiology of the pancreas is important for any discussion of type 2 diabetes. The pancreas is an organ that has both exocrine and endocrine functions. The endocrine tissue makes up only 1% to 5% of the total pancreatic mass in adults. It is randomly distributed throughout the exocrine pancreas, with a greater concentration in the head of the pancreas.1 The endocrine cells are arranged into units called islets of Langerhans. Each islet of Langerhans contains several types of cells, namely, alpha-, beta-, gamma-, and delta-cells. Beta-cells predominate and tend to be located in the center of the islet. Beta-cells make up approximately 70% to 80% of the islet mass. Gamma- and delta-cells constitute less than 10% of the islets. The alpha- and beta-cells both play important roles in glucose homeostasis.2 Beta-cells produce insulin and amylin, and alpha-cells produce glucagon. Both insulin and glucagon are essential for glucose homeostasis. When blood glucose is elevated after meals, beta-cells release insulin into the bloodstream. Alternatively, when blood glucose levels fall, alpha-cells release glucagon. These responses help maintain a normal glycemic state.”3,4Gamma- and delta-cells also produce important substances. Gamma-cells produce pancreatic polypeptide (PP) and delta-cells produce somatostatin.2 In studies, exogenous administration of pancreatic polypeptide reduced gastric acid secretion mediated by cholecystokinin and increased transit times in the intestine. Somatostatin’s actions are inhibitory. In the pituitary, it inhibits the secretion of growth hormone and thyrotropin, and in the pancreas, it inhibits insulin, glucagon, and pancreatic polypeptide. Somatostatin also inhibits several gut peptides and gastric acid secretion. Pancreatic exocrine secretion is also affected by both pancreatic polypeptide and somatostatin.5References:1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–281.2. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005: 21–39.3. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.4. Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–502.5. Boushey RP, Drucker DJ. Gastrointestinal hormones and gut endocrine tumors. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003:1777–1796.
12b- and a-Cells in the Pancreas of Normal Individuals b-Cellsa-CellsComprise about 70%–80% of the endocrine mass of the pancreas1,2Comprise about 15% of the endocrine mass of the pancreas1Located in the central portion of the islet1,2Located in the periphery of the islet1Produce insulin and amylin3Produce glucagon1Insulin released in response to elevated blood glucose levels1Glucagon released in response to low blood glucose levels1b- and α-Cells in the Pancreas of Normal IndividualsPancreatic islets of Langerhans occupy approximately 1% to 5% of the total pancreatic mass in human adults. They are randomly distributed throughout the exocrine pancreas but their density is slightly greater in the pancreatic head. Located within the pancreatic islets are endocrine cells known as pancreatic beta- and alpha-cells.1Beta-cells, which comprise about 70% to 80% of the endocrine mass of the pancreas, are located in the central portion of the islet. Beta-cells produce insulin, which is released in response to elevated blood glucose levels.2,3 The hormone amylin is also produced by beta-cells.4 Patients with type 2 diabetes exhibit some deficit in amylin production.4,5Alpha-cells, which comprise about 15% of the endocrine mass of the pancreas, are located in the periphery of the islets. Alpha-cells produce glucagon, which is released in response to low blood glucose levels.3Glucose homeostasis requires the integrated functioning of beta- and alpha-cells.61. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21– Rhodes CJ. Science. 2005;307:380–384.3. Kahn SE et al. Diabetes. 1998;47:640–645.References:1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–281.2. Rhodes CJ. Type 2 diabetes—a matter of β-cell life and death? Science. 2005;307:380–384.3. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir OC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:21–39.4. Kahn SE, Verchere CB, Andrikopoulos S, et al. Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans. Diabetes. 1998;47:640–645.5. Bryant E. Voice of the diabetic. Available at: Accessed October 14, 2005.6. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.
13Insulin Increases and Glucagon Falls in Response to Meals in Normal Subjects 180mg/dL ( - )Glucose12672400200pM ( )Insulin1057545ng/L ( )GlucagonInsulin Increases and Glucagon Falls in Response to Meals in Normal SubjectsThis slide depicts the changes in glucose, insulin, and glucagon concentrations after meal intake in subjects with normal glucose tolerance.The study measured glucose, insulin, and glucagon levels after ingestion of a 6-kcal/kg meal.1It demonstrated that after the meal, Glucose began to rise. Baseline level was 83 ± 1.8 mg/dL, which increased to 146 ± 7.2 mg/dL at 60 minutes. Glucose returned to baseline levels by 240 minutes.1Insulin followed a similar pattern.1Glucagon, however, dropped to a low by 90 minutes, then increased to a level above that of the baseline level.1–6060120180240300360Minutes After Meal IngestionN=11.Adapted with permission from Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.Reference:1. Woerle HJ, Meyer C, Dostou JM, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.
14Insulin and Glucagon Regulate Normal Glucose Homeostasis (alpha cell)Fasting stateFed statePancreasInsulin(beta cell)Insulin and Glucagon Regulate Normal Glucose HomeostasisNormal glucose homeostasis is maintained in large part through a feedback relationship between insulin, glucagon, and circulating glucose.1Fasting stateIn the fasting state, pancreatic alpha cells release glucagon.1,2 Glucagon release is triggered by a fall in the plasma glucose level.1 Concomitantly, the pancreatic beta cells secrete less insulin.Glucagon directs the liver to break down stored glycogen into glucose (glycogenolysis).1 The liver also generates new glucose (gluconeogenesis) during fasting. The end result is that the liver releases glucose into the bloodstream, thereby raising the plasma glucose level and maintaining homeostasis.Fed stateIn the fed state, glucose enters the bloodstream, and the beta cells detect the rise in glucose level and respond by promptly releasing insulin.1Insulin signals other tissues in the body to take in glucose to be used as energy or stored for later use.1 Insulin also signals the liver to decrease glucose production, thus suppressing hepatic glucose production. The net result is the lowering of the plasma glucose level.In the fed state, release of glucagon is suppressed, which also contributes to a decrease in glucose production.1Normal functioning of this feedback loop helps maintain glucose homeostasis.Glucose outputGlucose uptakeLiverBlood glucoseMuscleAdipose tissuePorte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.References:1. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med ;18:247–254.2. Unger RH. Glucagon and the insulin: Glucagon ratio in diabetes and other catabolic illnesses. Diabetes ;20:834–838.
16Insulin Sensitivity Index, Si x 10–5 min–1/pM Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects2,0001,5001,00050051015202595thMenWomen50thAIRglucose, pMAIRglucose = Acute (1st phase) insulin responseRelationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy SubjectsThe product of insulin sensitivity and insulin response provides a measure of beta-cell function. Any change in insulin sensitivity is balanced by a reciprocal and proportionate change in beta-cell function.1 The first-phase insulin response is a useful measure of beta-cell function because it is relatively independent of the steady-state plasma glucose level and can be quantified by administration of a maximal glucose bolus without glucose matching.2For glucose tolerance to remain constant as insulin sensitivity varies, a proportionate and reciprocal alteration in insulin output must occur.1A cohort of apparently healthy subjects younger than 45 years of age was studied to assess the relationship between AIRglucose, or first-phase insulin response, and insulin sensitivity (Si).2Insulin sensitivity is an estimate of the effect of insulin to augment the effect of hyperglycemia on glucose disposal.The percentiles for the relationship between insulin sensitivity and insulin response will be shown.[Advance build]The reference line is the 50th percentile.Percentiles above the 50th represent enhanced insulin response for the degree of insulin sensitivity. Reduced response is represented below the 50th percentile.1The relationship between insulin sensitivity and acute insulin response appears to be similar in both men and women.Compensatory β-Cell Insulin Secretion With Increasing Insulin ResistanceAn important factor affecting the magnitude of the insulin response is the prevailing degree of insulin sensitivity.1The relationship between insulin sensitivity and beta-cell function was examined in a cohort of healthy subjects under 45 years of age.Beta-cell secretory capacity was quantified as the acute insulin response to arginine at maximal glycemic potentiation or “AIRmax.”1,2Insulin sensitivity is an estimate of the effect of insulin to augment the effect of hyperglycemia on glucose disposal.2Percentiles above the 50th represent enhanced beta-cell secretory capacity for the degree of insulin sensitivity. Reduced response is represented below the 50th percentile.As shown by the graph, for glucose tolerance to remain constant when insulin sensitivity varies, any change in insulin sensitivity is balanced by a reciprocal and proportionate change in beta-cell response.1Therefore, the normal compensation for insulin resistance is an increase in insulin secretion by beta-cells.2Common causes of insulin resistance include genetic predisposition, obesity, inactivity, and aging.35thInsulin Sensitivity Index, Si x 10–5 min–1/pMAIRglucose=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.References:1. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.2. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and β-cell function in human subjects. Diabetes. 1993;42:1663–1672.
17Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 DiabetesStructural Changes in Islets With Type 2 DiabetesIn the normal pancreas, the exocrine cells make up the majority of the organ. The endocrine cells in the islets of Langerhans constitute about 1% to 5% of the pancreatic mass.1 There are between 300,000 and 1.5 million islets in the adult pancreas. Beta-cells, the insulin-producing cells, constitute approximately 70% to 80% of the islet mass.2 Beta-cell mass is determined by the balance between the production of beta-cells and the disappearance of beta-cells. The production of beta-cells is determined by the rates of neogenesis and replication. The disappearance of beta-cells is determined by the rate of cell death by necrosis or apoptosis.5In type 2 diabetes, there are structural changes in the islets of the pancreas. Up to 90% of patients with type 2 diabetes develop amyloid deposits between the capillaries and the islets. These deposits form cords that compress the islets.3 Amylin, also referred to as islet amyloid polypeptide, is the peptide constituting the deposits and is normally produced by beta-cells. Where amyloid deposits are found, reduction in beta-cell mass of the islet is also observed. However, it is not known whether amyloid deposits cause a reduction in the number of beta-cells. The role of amylin is still being investigated.4 Beta-cell mass may be affected by impaired neogenesis and proliferation of beta-cells. In patients with type 2 diabetes there is an increased frequency of beta-cell apoptosis, also known as programmed cell death.5,6 This process leads to a reduction in insulin production. This illustrates structural changes in islets with type 2 diabetes.References:1. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, Pa: Lea & Febiger; 1994:265–270.2. Cleaver O, Melton DA. Development of the endocrine pancreas. In: Kahn CR, Weir OC, King GL, Jacobson AM, Moses AC, Smith RJ, eds. Joslin’s Diabetes Mellitus. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:21–39.3. Roth J, Komminoth P, Klöppel G, Heitz PU. Diabetes and endocrine pancreas. In: Damjanov I, Linder J, eds. Anderson’s Pathology. 10th ed. St. Louis, Mo: Mosby-Year Book Inc. 1996:2042–2070.4. Leahy JL. β-cell dysfunction in type 2 diabetes mellitus. In: Kahn CR, Weir GC, eds. Joslin’s Textbook of Diabetes. 14th ed. Philadelphia, Pa: Lea & Febiger; 2005:449–461.5. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–110.6. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 2004;89:5535–5541.
18The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance1,2 Glucagon(α-cell)* Reduced effect of insulin indicating insulin resistancePancreasInsulin(β-cell)*The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin ResistanceThis diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis.In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1Most patients with type 2 diabetes have insulin resistance. Normally, pancreatic beta- cells increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1By the time of diagnosis of diabetes, beta-cell function has already decreased substantially and continues to decline over time.1Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production, which gives rise to an increase in blood glucose.1Likewise, with decreased secretion of insulin, there is less uptake of glucose by muscle and adipose tissue.2Glucose outputGlucose uptakeLiverHyperglycemiaMuscle1. 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. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.References:1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.2. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.
19Insulin resistance: A state in which a given concentration of insulin is associated with a subnormal glucose response (1)Syndrome X, Insulin Resistance Syndrome: Insulin resistance and compensatory hyperinsulinemia associated with glucose intolerance, hypertension, dyslipidemia, CVD.1-Moller DE & Flier JS, N Engl J Med 1991 Sep 26;325(13):2- Reaven G, Banting Lecture 1988
21Microvascular complications Natural History of DM 2Years fromdiagnosis-10-551015OnsetDiagnosisInsulin secretionInsulin resistancePostprandial glucoseFasting glucoseMicrovascular complicationsMacrovascular complicationsPre-diabetesType 2 diabetesAdapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ;Nathan DM. N Engl J Med ;347:
22First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes NormalType 2 Diabetes1201201001008080Plasma Insulin, µU/mL60Plasma Insulin, µU/mL604040First-Phase Insulin Response to IV Glucose Is Lost in Type 2 DiabetesIn this study, the release of insulin from beta-cells was measured in normal subjects and patients with type 2 diabetes after they were given an intravenous glucose tolerance test with 20-g boluses.1,2Normal subjects showed a sharp first-phase insulin response followed by persistent insulin secretion during the second phase, which lasts from 10 to 120 minutes.2However, patients with type 2 diabetes showed an absent first-phase response,1 with preservation of the second-phase insulin response.22020–30306090120–30306090120Time, minTime, minn=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.References:1. Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D Jr. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–502.2. Pfeifer MA, Halter JB, Porte D Jr. Insulin secretion in diabetes mellitus. Am J Med. 1981;70:579–588.
23Inadequate Insulin Secretion and Insulin Action Occur Prior to the Development of Type 2 Diabetes Overall Time EffectP<0.0001Overall Time EffectP<0.000130012**25010***2008**mg/kg EMBS/minM-High,AIRglucose, µ/mL1506Inadequate Insulin Secretion and Insulin Action Occur Early in the Development of Type 2 DiabetesDefects in insulin secretion and insulin action have been demonstrated in the progression from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes.1A longitudinal study was performed in 17 Pima Indians who progressed from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes over 5.1 ± 1.4 years.2Insulin secretion was measured after an IV glucose tolerance test using a 25-g IV bolus of glucose in 11 of 17 progressors.2AIRglucose is the acute insulin secretory response to IV glucose.2It was found that AIRglucose decreased by 27% during the progression from normal glucose tolerance to IGT and an additional 51% during the procession from impaired glucose tolerance to type 2 diabetes.2Insulin action was also assessed in this study using a 2-step hyperinsulinemic, euglycemic glucose clamp in which a low-dose priming continuous IV infusion of insulin was given for 100 minutes followed by a second high-dose infusion to achieve a steady-state plasma insulin concentration.2M-high is the maximally insulin-stimulated glucose disposal.2It was found that there was a 31% decrease in M-high during the progression from normal glucose tolerance to type 2 diabetes, indicating a decline in insulin action early in the disease process.2This study indicates that both insulin secretion and insulin action are affected early in the development of type 2 diabetes.21004502NGTIGTT2DMNGTIGTT2DMLongitudinal 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).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.References:1. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003;1427–1483.2. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–794.
24The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes10020030040050012345T2DMIGTNGTNonprogressorsProgressorsAIRglucose, μU/mLThe Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 DiabetesThis graph is from a longitudinal study performed over 5.1 ± 1.4 years in which a high-risk population, Pima Indians, with normal glucose tolerance (NGT) at baseline, were followed.1,2AIRglucose is the acute insulin response to glucose.2AIRglucose was measured relative to changes in insulin sensitivity, which was measured by the clamp technique.2M-low (on the x axis) represents total insulin stimulated glucose disposal at a low insulin concentration.2Measurements were made in 11 progressors—those individuals in whom glucose tolerance deteriorated from NGT to impaired glucose tolerance (IGT) to diabetes—and in 23 nonprogressors who maintained NGT throughout.2The lines represent the prediction line and the upper and lower limits of the 95% confidence interval.2There is a hyperbolic relationship between insulin secretion and insulin action in individuals with NGT. That is, insulin secretion increased with decreasing insulin action and vice versa.1Also, there is progressively impaired beta-cell function as a patient goes from NGT to IGT to type 2 diabetes (T2DM).2In this study, it was found that in the nonprogressors, AIRglucose increased with decreasing M-low; thus the individuals were able to maintain normal beta-cell function.1,2This indicates that the progressors had impaired beta-cell function.1,2However, although the progressors had a similar baseline AIRglucose to nonprogressors relative to their degree of insulin resistence, AIRglucose was already too low; thus the individuals fell below the 95th confidence interval while still maintaining NGT.1M-Low, mg/kg EMBS/minN=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.References:1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787–794.2. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.
26Pathophysiology of Type 2 Diabetes In summary:The pathophysiology of type 2 diabetes includes islet cell dysfunction, insulin resistance, and increased hepatic glucose output.1–3Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin.1Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time.1Inside the Islet: Exploring Issues in Type 2 DiabetesIn summary:The pathophysiology of type 2 diabetes includes beta-cell dysfunction, insulin resistance, and increased hepatic glucose output.1–3Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin.1Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time.11. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.2. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775– Del Prato S, Marchetti P. Diabetes Technol Ther. 2004;6:719–731.References:1. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med. 1995;18:247–254.2. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781.3. Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: the role of thiazolidinediones. Diabetes Technol Ther. 2004;6:719–731.
27Treatment Options in Type 2 Diabetes Why treat diabetes?Therapeutic Lifestyle ChangesOral medicationsInsulinNewer agents (incretins)Gastric Bypass
28Higher Blood Sugar Causes More Complications Relative RiskRetinopathyNephropathyNeuropathyMicroalbuminuriaHbA1c (%)15131197531681012Based on DCCT follow-upEndocrinol Metab Clin North Am. 1996;25:
29Intensive Therapy Group Various Endpoints in the UKPDS ComplicationReduction in RiskAll microvascular25% P<0.01– Retinopathy progression21% P<0.02– Microalbuminuria33% P<0.0001Myocardial infarction16% P=0.052UKPDS data, nearly 4000 patients for intensively treated groups, no difference between SU or insulinAll diabetes-related endpoints studied12% P<0.03UKPDS Group. Lancet. 1998;352:
30Intensive initial treatment with insulin, sulfonylurea in type 2 DM reduces microvascular and macrovascular complications and death
32Major Targeted Sites of Oral Drug Classes PancreasBeta-cell dysfunctionSulfonylureasMuscle and fatMeglitinidesLiverHepatic glucose overproduction↓Glucose levelInsulin resistanceMajor Targeted Sites of Various Oral Drug ClassesSpeaker notesThe various therapeutic agents currently available for the treatment of type 2 diabetes act on different pathways to control hyperglycemi.1,2[Slide build for each drug class]Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1Meglitinides, another class of short-acting insulin secretagogue, also act in the pancreas, stimulating insulin release by binding to several sites on the beta-cells. They are used to control postprandial hyperglycemia.1TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. It also enhances insulin sensitivity in muscle.1,3Based on the different mechanisms of action of these agents, these drugs may be used in combination, as noted in the prescribing information for each product.1,2Purpose:To provide a high-level overview of the key mechanisms and target sites for the currently available antihyperglycemic classes.Takeaway:Different drug classes with different and complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and maximize A1C control.GutBiguanidesTZDsTZDsBiguanidesReduced glucose absorptionAlpha-glucosidase inhibitorsTZD = thiazolidinediones.DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003:1427–1483.References1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.
34Modern insulin syringes, pens, delivery devices, rapid-acting insulin analogs Modern insulin syringes with very fine needles (gauges range from 27-31)Insulin pens allow patient to inject and carry insulin discreetlyInnolet device is a pre-filled insulin doser, easy to read with audible clicksNeedle-free delivery systemsNew rapid-acting insulin analogs simulate physiologic insulin profiles allowing for greater flexibility with meal timing, carbohydrate content, etc.
35Insulin delivery systems on the horizon... Inhaled insulin – Came and went….
36Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. Incretin OverviewAn incretin is a hormone with the following characteristics1:It is released from the intestine in response to ingestion of food, particularly glucose.The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin.The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent).Incretin OverviewMany of you already are somewhat familiar with incretins and their role. For the benefit of those who are not, let’s briefly consider, what are incretins?IncretinsAre intestinal hormones released after meal ingestionPlay an important role in glucose homeostasisPhysiologically help regulate insulin release in a glucose-dependent mannerMeier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
38GLP-1 and GIP Are Incretin Hormones Is released from L cells in ileum and colon1,2Is released from K cells in duodenum1,2Stimulates insulin response from beta cells in a glucose-dependent manner1Inhibits gastric emptying1,2Has minimal effects on gastric emptying2Reduces food intake and body weight2Has no significant effects on satiety or body weight2Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1Does not appear to inhibit glucagon secretion from alpha cells1,2 (may even stimulate glucagon!)GLP-1 and GIP Are Incretin HormonesGLP-1 and GIP are the currently identified incretin hormones.GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner.GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.GLP-1: glucagon-like peptide-1GIP: glucose-dependent insulinotropicPolypeptide (formerly gastric inhibitoryPolypeptide!)1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.References:1. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.2. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206.4. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
40GLP-1 and GIP Are Degraded by the DPP-4 Enzyme MealIntestinal GIP and GLP-1 releaseDPP-4EnzymeGIP-(1–42)GLP-1(7–36)IntactGIP-(3–42)GLP-1(9–36)MetabolitesGLP-1 and GIP Are Degraded by the DPP-4 EnzymeGLP-1 and GIP have short biological half-lives; they are rapidly degraded by DPP-4.1–3DPP-4 is a widely expressed enzyme present on cells in many tissues, including the kidney, GI tract, biliary tract and liver, placenta, uterus, prostate, skin, lymphocytes, and endothelial cells (which may be involved in the inactivation of circulating peptides).4Rapid InactivationHalf-life*GLP-1 ~ 2 minutesGIP ~ 5 minutesGIP and GLP-1 ActionsDeacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.References:1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.2. Kieffer TJ, McIntosh CHS, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology ;136:3585–3596.3. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80:952–957.4. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100.
42The Beginning Exenatide Synthetic version of salivary protein (exendin-4) found in the Gila monsterMore than 50% amino acid sequence identity with human GLP-1Binds to known human GLP-1 receptors on cells (in vitro)Resistant to DPP-IV inactivationDISCUSSION POINTS:Exenatide, which was discovered in the salivary secretions of the Gila monster, has 53% amino acid sequence identity with mammalian GLP-1Exenatide binds in vitro to the known human GLP-1 receptors on cells and mimics multiple glucoregulatory effects of GLP-1The amino acid at position 2, the site of DPP-IV inactivation on the GLP-1 molecule, is different in exenatide – making exenatide resistant to DPP-IV enzymatic degradationAfter a single subcutaneous (SC) injection, exenatide can be measured in the plasma for up to 10 hoursSLIDE BACKGROUND:Following exenatide SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hoursThe mean terminal half-life of exenatide is 2.4 hoursPharmacokinetic characteristics of exenatide are independent of the doseIn most individuals, exenatide concentrations are measurable for approximately 10 hours post-doseSite of DPP-IV InactivationFollowing injection, exenatide is measurable in plasma for up to 10 hoursAdapted from Nielsen LL, et al. Regul Pept. 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:
43Exenatide Lowered A1C Large Phase 3 Clinical Studies Type 2 DiabetesPlacebo BID5 µg Exenatide BID10 µg Exenatide BIDMETSFUMET + SFU0.50.50.50.20.10.1DISCUSSION POINTS:Significant A1C reductions were seen with the 5-µg and 10-µg exenatide treatment arms in all three studies (P<0.005 vs placebo)The A1C lowering in the 10-µg arm was greater than in the 5-µg arm (P<0.05)Baseline A1C: placebo group = 8.5%; 5-µg exenatide BID treatment arm = 8.4%; 10-µg exenatide BID treatment arm = 8.5%Exenatide is associated with reduced A1C no matter the background oral therapy (MET and/or SFU), and disease duration (SFU + MET study patients had longer disease duration)SLIDE BACKGROUND:Three 30-week, placebo-controlled, double-blind, Phase 3 studies; patients with type 2 diabetes randomized to placebo or 5 µg or 10 µg exenatide BID with MET and/or SFU, N = 1446Combined pivotals: MET, SFU, MET + SFU; 30-week, double-blind, Phase 3 studies; ITT patients with type 2 diabetes were randomized to placebo (n = 483), 5 µg exenatide BID (n = 480), or 10 µg exenatide BID (n = 483). The LOCF method was applied to the dataIndividual pivotalsMET (placebo [n = 113 and baseline A1C = 8.2], 5 µg exenatide BID [n = 110 and baseline A1C = 8.3], 10 µg exenatide BID [n = 113 and baseline A1C = 8.2])SFU (placebo [n = 123 and baseline A1C = 8.7], 5 µg exenatide BID [n = 125 and baseline A1C = 8.5], 10 µg exenatide BID [n = 129 and baseline A1C = 8.6])MET + SFU (placebo [n = 247 and baseline A1C = 8.5], 5 µg exenatide BID [n = 245 and baseline A1C = 8.5], 10 µg exenatide BID [n = 241 and baseline A1C = 8.5])-0.5**-0.9-0.6**-0.8A1C (%)-0.5-0.5-0.5-0.4*- 0.8-1-1-1*ITT; N = 1446; Mean ± SE; *P<0.005 Data from DeFronzo RA, et al. Diabetes Care. 2005;28: ; Data from Buse JB, et al. Diabetes Care. 2004; 27: ; Data from Kendall DM, et al. Diabetes Care. 2005;28:
44insulin from beta cells Glucose uptake by muscles SummaryGI tractPancreas2,3insulin from beta cells(GLP-1 and GIP)Glucose-dependent2,4Ingestion of foodGlucose uptake by musclesRelease of gut hormones — Incretins1,2β-cellsα-cellsBlood glucoseActiveGLP-1 & GIPGlucose production by liverXSummaryAfter food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).1–3 Under normal circumstances, DPP-4 rapidly degrades these incretins to their inactive forms after their release into the circulation.1,2Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.2,3 The subsequent increase in glucose uptake in muscles3,4 and reduced glucose output from the liver2 help maintain glucose homeostasis.Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.2,3 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.2,5Glucagon from alpha cells(GLP-1)Glucose dependentDPP-4 EnzymeInactive GLP-1and GIPActive incretins physiologically regulate glucose by modulating insulin secretion in a glucose-dependent manner.GLP-1 also modulates glucagon secretion in a glucose-dependent manner.1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.2. Ahrén B. Curr Diab Rep. 2003;2:365–372.3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.References:1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.2. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.4. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.5. Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.
45Clinical Pharmacology of JANUVIA (sitagliptin phosphate): Pharmacodynamics:JANUVIA led to inhibition of DPP-4 activity for a 24-hour period in patients with type 2 diabetes, resulting in:2- to 3-fold in levels of active GLP-1 and GIP glucagon concentrations responsiveness of insulin release to glucose fasting glucose and glucose excursion after an oral glucose load or a mealIn healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemiaClinical Pharmacology of JANUVIA™ (sitagliptin phosphate): PharmacodynamicsIn patients with type 2 diabetes, administration of single oral doses of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After a meal, DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher insulin and C-peptide concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.In healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.
46Diabetes and Bariatric Surgery Buchwald et al (2004), in a meta-analysis of 22,094 patients undergoing gastric bypass surgery for morbid obesity found:1417 of 1846 patients with diabetes (76.8%) experienced complete resolution of their diabetes(Defined as ability to discontinue all diabetes-related medications and maintain blood glucose levels within the normal range)
47Summary1. Type 2 Diabetes (DM 2) is a multi-factorial disorder that is increasing in prevalence.2. Insulin resistance, beta-cell & alpha-cell dysfunction and abnormal incretin function all contribute to the metabolic derangements seen in pre-diabetes and DM2.3. Diabetes is associated with increase in both microvascular and macrovascular complications4. Many therapeutic options exist to target the pathophysiologic features of DM 2, reduce hyperglycemia and can prevent/delay complications.