Pathophysiology of type 2 diabetes mellitus R. Leibel Naomi Berrie Diabetes Center 19 March 2010
Body Mass Index Chart 25-29.9 29.9 = overweight; 30-39.9= 39.9 obese; >40= extreme obesity 5'0" 5'2" 52 5'4" Weight (lbs) 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 Height 5'6" 5'8" 5'10" 6'0" 6'2" 6'4"
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) 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 29.0 30.9 31.0 32.9 33.0 34.9 ³35.0 BMI (kg/m 2 ) Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7.
7.8 % of U.S. Population >20yo have diabetes. Diagnosed: 17.9 million Undiagnosed: 5.7 million 20 yo. 23.5 Million 60 yo. 12.2 Million 11.2 % M; 10.2% F Non-his white: 9.8% Non-his black: 14.7%
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
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
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 100 125 mg/dl Impaired Glucose Tolerance: OGTT 2hr plasma glucose p p g 140 199 mg/dl
Complications of Diabetes. I. Heart disease & stroke: 2-4x increase Hypertension: in 75% Blindness: leading cause 20-74 yo Kidney disease: 44% all new cases CNS/PNS: ~70% Amputations: 60% all non traumatic LL Periodontal disease Pregnancy, fetal malformation Psychiatric
Complications of Diabetes. II. Insulin Resistance: Large and medium vessel coronary, peripheral, and brain ischemia Hyperglycemia: y Small Vessel glomerulopathy, retinopathy, neuropathy
Predisposing Genes Predisposing Genes Predisposing Environment Obesity Type 2 Diabetes 80% diabetic are obese 50% obese are diabetic i
Figure 1
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
Obici et al. Nature Medicine. 8:1396, 2002
Muscle Liver Petersen & Shulman AJP 2006
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
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 =09 0.9, P<10 10 4 Subcutaneous: r 2 = 0.39, P < 0.01 Weisberg et al., JCI, Dec 2003
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
A hypothetical model for postnatal pancreatic {beta}-cell growth in humans C. J. Rhodes Science 307, 380-384 (2005)
Butler AE, et al. Diabetes 2003
Intrauterine Effects on Risk T2D
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 M High
Diabetes Prevalence (%) in Offspring by Mother s Diabetes at Pregnancy 90 80 70 60 50 40 30 20 10 0 Nondiabetic 60 Prediabetic Diabetic 5-9 10-14 15-19 20-24 25-29 Age (years)
Kahn SE et al. Nature 2006
DPPT
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.
prior candidates TCF2, SLC30A8 not on this affy array Frayling. Nature Reviews. Genetics. 8:657, 2007 from Zeggini et al. Science. 316:1336, 2007
Florez. J. Clin Endocrin Metab. 2008
Cauchi S et al. Journal of Molecular Medicine 2007
Kahn SE et al. Nature 2006
DIABETES SPECTRUM: Gene x Environment Vaxillaire. Endocrine Reviews. 2008
[11C] DTBZ and PET visualizes the human pancreas
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