Pathophysiology of type 2 diabetes mellitus R. Leibel Naomi Berrie Diabetes Center 25 February 2008 Body Mass Index Chart 25-29.9 = overweight; 30-39.9= obese; >40= extreme obesity 5'0" 5'2" Weight (lbs) 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 5'4" Height 5'6" 5'8" 5'10" 6'0" 6'2" 6'4" 1
Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and 2001 1986 -> 2000. BMI > 30 2x; >40 4x; > 50 6x. Mokdad, A. H. et al. JAMA 2003;289:76-79 Relative Risk of Type 2 Diabetes in US Women According to BMI Relative risk (age-adjusted) 100 80 60 40 20 0 Bars represent 95% confidence intervals <22.0 22.0 22.9 23.0 23.9 24.0 24.9 25.0 26.9 27.0 28.9 BMI (kg/m 2 ) 29.0 30.9 31.0 32.9 33.0 34.9 ³35.0 Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7. 2
Plasma Glucose and Insulin Profiles After Oral Glucose Challenge Reaven GM et al. Diabetologia. 1977;13:201-206. 3
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Millions of Cases of Diabetes in 2000 and Projections for 2030, with Projected Percent Changes Hossain P et al. N Engl J Med 2007;356:213-215 5
Clinical definition of diabetes Plasma glucose > 200 mg/dl at any time or Fasting (post-absorptive) plasma glucose > 125 mg/dl or 2 hour post-75gm oral glucose load plasma glucose > 200 mg/dl Diab. Care; 23:381, 2000 6
Clinical Definition Impaired Glucose Tolerance Fasting (post-absorptive) plasma glucose: 100-125 mg/dl or 2 hr (OGTT) plasma glucose: 140-199 mg/dl Diab. Care; 23:381, 2000 & update 4 04 Predisposing Genes Predisposing Genes Predisposing Environment Obesity Type 2 Diabetes 80% diabetic are obese 50 % obese are diabetic 7
Figure 1 8
In the absence of insulin, GLUT4 is localized to an intracellular compartment GLUT1 GLUT1 Membrane GLUT4 Nucleus In the presence of insulin, GLUT4 translocates to the plasma membrane GLUT1 GLUT4 IRS Membrane PI 3-K AKT? PKC GLUT4 Translocation Nucleus 9
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Obici et al. Nature Medicine. 8:1396, 2002 Potential rate-controlling steps in insulin-mediated muscle glycogen synthesis 11
Mechanisms FFA-induced insulin resistance in skeletal muscle Randle Shulman 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 12
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 Adipose tissue macrophages Perigonadal: r 2 = 0.7, P < 10 4 Perirenal: r 2 = 0.7, P < 10 4 Mesenteric: r 2 = 0.9, P < 10 4 Subcutaneous: r 2 = 0.39, P < 0.01 Weisberg et al., JCI, Dec 2003 13
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 14
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Prospective Analysis 8 Year Cumulative Incidence (%) of Type 2 Diabetes in Pima Indians 317 NGT/62 Diabetics 50 40 (%) 30 20 10 0 Low Mid High AIR Low Mid High M Diabetes Prevalence (%) in Offspring by Mother s Diabetes at Pregnancy 90 80 70 60 50 40 30 20 10 0 Nondiabetic Prediabetic Diabetic 5-9 10-14 15-19 20-24 25-29 Age (years) 16
Kahn SE et al. Nature 2006 Longitudinal Study of the Transition from NGT to Type 2 Diabetes Early Insulin Response vs Insulin Action 400 AIR (uu/ml) 300 200 100 IGT DIA NGT N=17 NGT N=3 NGT 1 NGT 0 0 1 2 3 4 M-low (mg/kg-embs/min) Adapted from Weyer et al, 1999 17
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DPPT 19
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;299:316-323. Copyright restrictions may apply. 20
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Kahn SE et al. Nature 2006 22
Diabetes-susceptibility QTLs Chr1 Chr2 Chr5 Chr8 Chr14 Chr17 23
Do beta cells in D/D animals replicate as well as beta cells in B/B animals? B/B: D/D: 60x 20x 24
Zebrafish prior candidates TCF2, SLC30A8 not on this affy array Frayling. Nature Reviews. Genetics. 8:657, 2007 from Zeggini et al. Science. 316:1336, 2007 25
Cauchi S et al. Journal of Molecular Medicine 2007 [11C] DTBZ and PET visualizes the human pancreas 26
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