R. Leibel Naomi Berrie Diabetes Center 19 March 2010

Transcription

1 Pathophysiology of type 2 diabetes mellitus R. Leibel Naomi Berrie Diabetes Center 19 March 2010

2 Body Mass Index Chart = overweight; = 39.9 obese; >40= extreme obesity 5'0" 5'2" 52 5'4" Weight (lbs) Height 5'6" 5'8" 5'10" 6'0" 6'2" 6'4"

3 Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and > BMI > 30 2x; >40 4x; > 50 6x. Mokdad, A. H. et al. JAMA 2003;289:76-79

4 Relative Risk of Type 2 Diabetes in US Women According to BMI Relative risk (age-adjusted) adjusted) Bars represent 95% confidence intervals < ³35.0 BMI (kg/m 2 ) Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7.

5 7.8 % of U.S. Population >20yo have diabetes. Diagnosed: 17.9 million Undiagnosed: 5.7 million 20 yo Million 60 yo Million 11.2 % M; 10.2% F Non-his white: 9.8% Non-his black: 14.7%

6 Millions of Cases of Diabetes in 2000 and Projections for 2030, with Projected Percent Changes Hossain P et al. N Engl J Med 2007;356:

7 Definition of Type 2 Diabetes (earlier NIDDM) 90 95% all diabetes Beta cell diathesis exacerbated by obesity & inactivity Relative hypoinsulinemia Strong family Hx and Hx gestational ti diabetes Race/ethnicity: American indians, Hispanic/Latino, African-American, Asians/Pacific islanders: These groups also showing increase in T2D in childhood

8 OertDiabetes Overt Mellitus Fasting plasma glucose 126 mg/dl Casual plasma glucose 200 mg/dl 2hr OGTT plasma glucose 200 mg/dl Impaired Glucose Homeostasis Impaired Fasting Glucose: FPG mg/dl Impaired Glucose Tolerance: OGTT 2hr plasma glucose p p g mg/dl

9 Complications of Diabetes. I. Heart disease & stroke: 2-4x increase Hypertension: in 75% Blindness: leading cause yo Kidney disease: 44% all new cases CNS/PNS: ~70% Amputations: 60% all non traumatic LL Periodontal disease Pregnancy, fetal malformation Psychiatric

10 Complications of Diabetes. II. Insulin Resistance: Large and medium vessel coronary, peripheral, and brain ischemia Hyperglycemia: y Small Vessel glomerulopathy, retinopathy, neuropathy

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12 Predisposing Genes Predisposing Genes Predisposing Environment Obesity Type 2 Diabetes 80% diabetic are obese 50% obese are diabetic i

13 Figure 1

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15 In the absence of insulin, GLUT4 is localized to an intracellular compartment GLUT1 GLUT1 Membrane GLUT4 Nucleus

16 In the presence of insulin, GLUT4 translocates to the plasma membrane GLUT1 GLUT4 IRS Membrane PI 3-K AKT? PKC GLUT4 Translocation Nucleus

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19 Obici et al. Nature Medicine. 8:1396, 2002

20 Muscle Liver Petersen & Shulman AJP 2006

21 Adipose tissue is an endocrine organ. Lean adipose tissue acrp30 Muscle acrp30 Obese adipose tissue TNFα Liver TNFα IL-6 leptin Brain IL-6 leptin

22 In obese mice, adipose tissue macrophages have an unusual morphology: lipid vacuoles, multinucleated. Lean 16- week BL6 female, omental fat ob/ob 16- week BL6 female, omental fat Weisberg et al., JCI, Dec 2003

23 Adipose tissue macrophages Perigonadal: r 2 = 0.7, P < 10 4 Perirenal: r 2 = 0.7, P < 10 4 Mesenteric: r 2 =09 0.9, P< Subcutaneous: r 2 = 0.39, P < 0.01 Weisberg et al., JCI, Dec 2003

24 Improved insulin sensitivity in Ccr2 -/- mice Insulin tolerance test Glucose tolerance test = Ccr2 +/+ with dietary obesity; 44% body fat = Ccr2 -/- with dietary obesity; 45% body fat

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26 A hypothetical model for postnatal pancreatic {beta}-cell growth in humans C. J. Rhodes Science 307, (2005)

27 Butler AE, et al. Diabetes 2003

28 Intrauterine Effects on Risk T2D

29 Prospective Analysis 8 Year Cumulative Incidence (%) of Type 2 Diabetes in Pima Indians 317 NGT/62 Diabetics (%) Low Mid High AIR Low Mid M High

30 Diabetes Prevalence (%) in Offspring by Mother s Diabetes at Pregnancy Nondiabetic 60 Prediabetic Diabetic Age (years)

31 Kahn SE et al. Nature 2006

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34 DPPT

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36 Percentage of Weight Loss Achieved Over the 2-Year Study Period (n = 60) and Individual Weight Measures at Baseline and at 2 Years Dixon, J. B. et al. JAMA 2008;299: Copyright restrictions may apply.

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38 prior candidates TCF2, SLC30A8 not on this affy array Frayling. Nature Reviews. Genetics. 8:657, 2007 from Zeggini et al. Science. 316:1336, 2007

39 Florez. J. Clin Endocrin Metab. 2008

40 Cauchi S et al. Journal of Molecular Medicine 2007

41 Kahn SE et al. Nature 2006

42 DIABETES SPECTRUM: Gene x Environment Vaxillaire. Endocrine Reviews. 2008

43 [11C] DTBZ and PET visualizes the human pancreas

44 END