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Type 2 Diabetes: Pathophysiology and Opportunities for Treatment Tyler Aguinaldo, MD Director, Center for Diabetes & Metabolism Santa Clara Valley Medical.

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Presentation on theme: "Type 2 Diabetes: Pathophysiology and Opportunities for Treatment Tyler Aguinaldo, MD Director, Center for Diabetes & Metabolism Santa Clara Valley Medical."— Presentation transcript:

1 Type 2 Diabetes: Pathophysiology and Opportunities for Treatment Tyler Aguinaldo, MD Director, Center for Diabetes & Metabolism Santa Clara Valley Medical Center April 16, 2009

2 Objectives Review epidemiology of diabetes and pre-diabetes. Review epidemiology of diabetes and pre-diabetes. Distinguish diabetes type 1 and type 2 Distinguish diabetes type 1 and type 2 Describe the role of pancreatic islet cells (  and β) in maintaining normal glucose homeostasis. Describe 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. 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. Summarize treatment options in type 2 diabetes.

3 Number (in Millions) and Percent of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, U.S., 1980–2006 gpersons.htm

4 4 National 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 people Undiagnosed: 5.7 million people Prevalence of Impaired Fasting Glucose in People Aged 20 Years or Older, United States, 2007 In 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

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6 The global diabetes epidemic 2000―2010 and beyond: prevalence of diabetes Wild S, et al. Diabetes Care 2004;27:1047―53. Adapted from Zimmet P, et al. Nature 2001;414:782 ― % % % % % % 2000: 151 million 2010: 220 million + ~50% 2025: 300 million + ~100% 2030: 366 million + ~145% URGENT NEED FOR ACTION

7 NHANES: Glycemic Control in the U.S. A1C <7% A1C >7% 20.8M Patients 38% 62% 12.6M Treated With Oral Agents or Insulin 6.2M Undiagnosed 12.6M Rx Treated 2M D&E CDC 2005, NHANES 1999–2002 NHANES 1999– NHANES 1988– Yet Average A1C Is Increasing Yet Average A1C Is Increasing AACE A1C Goal =  6.5% ADA A1C Goal = <7% AACE A1C Goal =  6.5% ADA A1C Goal = <7%

8 Criteria for the Diagnosis of Diabetes

9 Two Main Classes of Diabetes Mellitus Type 1 Diabetes: Type 1 Diabetes: –Insulin deficiency (usually auto-immune) –Accounts for 5-10% of total diabetes Type 2 Diabetes: Type 2 Diabetes: –Multi-factorial: Insulin resistance Insulin resistance Relative insulin deficiency Relative insulin deficiency Dysregulation of glucagon Dysregulation of glucagon Abnormalities in incretin hormones Abnormalities in incretin hormones –Accounts for 90-95% of total diabetes –Associated with “Metabolic Syndrome”

10 Older Older Overweight Overweight Insulin-resistant Insulin-resistant High TG’s/Low HDL-C High TG’s/Low HDL-C Younger Younger More lean More lean Insulin-deficient Insulin-deficient Low triglycerides Low triglycerides Type 1 DM Type 2 DM

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12 12  - and  -Cells in the Pancreas of Normal Individuals  -Cells  -Cells  Comprise about 70%–80% of the endocrine mass of the pancreas 1,2  Comprise about 15% of the endocrine mass of the pancreas 1  Located in the central portion of the islet 1,2  Located in the periphery of the islet 1  Produce insulin and amylin 3  Produce glucagon 1  Insulin released in response to elevated blood glucose levels 1  Glucagon released in response to low blood glucose levels 1 1. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21– Rhodes CJ. Science. 2005;307:380– Kahn SE et al. Diabetes. 1998;47:640–645.

13 13 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 – mg/dL ( - ) Glucose pM ( - ) Insulin ng/L ( - ) Glucagon

14 14 Blood glucose  Insulin and Glucagon Regulate Normal Glucose Homeostasis Glucose output Glucose uptake Glucagon (alpha cell) Insulin (beta cell) Pancreas Liver Muscle Adipose tissue Fasting stateFed state   Porte 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.

15 15 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, Time, min Plasma Insulin, pmol/L 1st phase

16 16 Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects Men Women 2,000 1,500 1, th 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

17 17 Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes

18 18 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– 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. The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance 1,2 * *Reduced effect of insulin indicating insulin resistance

19 19 Insulin 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): Reaven G, Banting Lecture 1988

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21 21 Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med. 2002;347: Natural History of DM 2 Type 2 diabetes Years from diagnosis Pre-diabetes Onset Diagnosis Insulin secretion Insulin resistance Postprandial glucose Macrovascular complications Fasting glucose Microvascular complications

22 22 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 – Time, min – Time, min Plasma Insulin, µU/mL

23 23 Inadequate Insulin Secretion and Insulin Action Occur Prior to 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– NGT AIRglucose, µ/mL IGTT2DM Overall Time Effect P< NGT M-High, mg/kg EMBS/min IGTT2DM Overall Time Effect P< * **  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).

24 24 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 T2DM IGT NGT Nonprogressors Progressors The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes

25 25 Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes – 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.

26 26 Pathophysiology of 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 Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247– Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775– Del Prato S, Marchetti P. Diabetes Technol Ther. 2004;6:719–731.

27 27 Treatment Options in Type 2 Diabetes 1. Why treat diabetes? 2. Therapeutic Lifestyle Changes 3. Oral medications 4. Insulin 5. Newer agents (incretins) 6. Gastric Bypass

28 Higher Blood Sugar Causes More Complications Endocrinol Metab Clin North Am. 1996;25: Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria HbA 1c (%)

29 UKPDS Group. Lancet. 1998;352: Intensive Therapy Group Various Endpoints in the UKPDS 33% P < % P <0.02 – Microalbuminuria – Retinopathy progression Complication Reduction in Risk All microvascular 25% P <0.01 Myocardial infarction All diabetes-related endpoints studied 16% P = % P <0.03

30 Intensive initial treatment with insulin, sulfonylurea in type 2 DM reduces microvascular and macrovascular complications and death

31 DietExercise Therapeutic Lifestyle Changes (TLC)

32 Major Targeted Sites of Oral Drug Classes TZD = 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. Pancreas ↓ Glucose level Gut Alpha- glucosidase inhibitors Muscle and fat Liver TZDs Biguanides Sulfonylureas Meglitinides Beta-cell dysfunction Reduced glucose absorption Hepatic glucose overproduction Insulin resistance TZDs

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34 Modern insulin syringes, pens, delivery devices, rapid-acting insulin analogs

35 Insulin delivery systems on the horizon... Inhaled insulin – Came and went….

36 36 Incretin Overview  An incretin is a hormone with the following characteristics 1 : –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). Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

37 37 Time, min IR Insulin, mU/L nmol/L The Incretin Effect in Subjects With & W/O DM2 Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol / L Oral glucose load Intravenous (IV) glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes. Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

38 38 GLP-1 and GIP Are Incretin Hormones GLP-1GIP  Is released from L cells in ileum and colon 1,2  Is released from K cells in duodenum 1,2  Stimulates insulin response from beta cells in a glucose-dependent manner 1  Inhibits gastric emptying 1,2  Has minimal effects on gastric emptying 2  Reduces food intake and body weight 2  Has no significant effects on satiety or body weight 2  Inhibits glucagon secretion from alpha cells in a glucose-dependent manner 1  Does not appear to inhibit glucagon secretion from alpha cells 1,2 (may even stimulate glucagon!) 1.Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587– Drucker DJ. Diabetes Care. 2003;26:2929–2940. GLP-1: glucagon-like peptide-1GIP: glucose-dependent insulinotropic Polypeptide (formerly gastric inhibitory Polypeptide!)

39 39 Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decreases. *P <0.05 Patients with type 2 diabetes (N=10) mmol/L mg/dL * * * * * * * pmol/L mU/L * * * * * * Infusion Minutes pmol/L * * * * pmol/L Placebo GLP-1 Insulin Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. –30

40 40 GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal Intestinal GIP and GLP-1 release GIP and GLP-1 Actions DPP-4 Enzyme GIP-(1–42) GLP-1(7–36) Intact GIP-(3–42) GLP-1(9–36) Metabolites Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes Deacon CF et al. Diabetes. 1995;44:1126–1131. *Meier JJ et al. Diabetes. 2004;53:654–662.

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42 The Beginning Exenatide –Synthetic version of salivary protein (exendin-4) found in the Gila monster –More than 50% amino acid sequence identity with human GLP-1  Binds to known human GLP-1 receptors on  cells (in vitro)‏  Resistant to DPP-IV inactivation Following injection, exenatide is measurable in plasma for up to 10 hours Site of DPP-IV Inactivation Adapted from Nielsen LL, et al. Regul Pept. 2004;117: Adapted from Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:

43 * -0.6 * * -0.8 * -0.9 SFU Exenatide Lowered A1C Large Phase 3 Clinical Studies Placebo BID 5 µg Exenatide BID 10 µg Exenatide BID MET + SFU 0.2 MET -0.4 * *  A1C (%)‏ 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: Type 2 Diabetes

44 44 Summary Ingestion of food Pancreas 2,3 β-cells α -cells Release of gut hormones — Incretins 1,2 insulin from beta cells (GLP-1 and GIP) Glucose-dependent Glucose uptake by muscles Glucose production by liver Blood glucose Glucagon from alpha cells (GLP-1) Glucose dependent Active incretins physiologically regulate glucose by modulating insulin secretion in a glucose-dependent manner. GLP-1 also modulates glucagon secretion in a glucose-dependent manner. GI tract Active GLP-1 & GIP Inactive GLP-1 and GIP DPP-4 Enzyme 2,4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876– Ahrén B. Curr Diab Rep. 2003;2:365– Drucker DJ. Diabetes Care. 2003;26:2929– Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. X

45 45 Clinical 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 meal  In healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia

46 Diabetes and Bariatric Surgery Buchwald et al (2004), in a meta-analysis of 22,094 patients undergoing gastric bypass surgery for morbid obesity found: 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 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) (Defined as ability to discontinue all diabetes- related medications and maintain blood glucose levels within the normal range)

47 Summary 1. Type 2 Diabetes (DM 2) is a multi-factorial disorder that is increasing in prevalence. 1. 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. 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 complications 3. Diabetes is associated with increase in both microvascular and macrovascular complications 4. Many therapeutic options exist to target the pathophysiologic features of DM 2, reduce hyperglycemia and can prevent/delay complications. 4. Many therapeutic options exist to target the pathophysiologic features of DM 2, reduce hyperglycemia and can prevent/delay complications.

48 Thanks! Questions?


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