Pathophysiology of type 2 diabetes mellitus R. Leibel Naomi Berrie Diabetes Center 26 February 2007 Body Mass Index Chart 25-29.9 = overweight; 30-39.9= obese; >40= extreme obesity 5'0" 5'2" 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" 1
Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and 2001 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 35.0 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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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 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 6
Predisposing Genes Predisposing Genes Predisposing Environment Obesity Type 2 Diabetes 80% diabetic are obese 50 % obese are diabetic Figure 1 7
Insulin action Insulin Insulin Receptor shc Cap RAS SOS GRB2 IRS Cbl Crk II Glucose Uptake RAF MAPKK PI 3-K PKC Glycogen Synthesis MAPK GSK3 SGK AKT p70s6k BAD Foxo Gene Expression PDE3b Protein Synthesis Anti-lipolysis Cell survival 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 TNF Liver TNF 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
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 15
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
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
DPPT 18
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Genome-wide linkage studies for T2DM in humans GLUT1 Leptin receptor 2p24 2p21 HK2 3p24 Wolframin 1q21-24 1q42 Lamin A/C IRS1 2q37 CAPN10 NeuroD1 5q13 PPARg 4q34 p85a GLUT2 FABP ADRB2b 3q27 5q31 PC-1 GCK PP1G 7q21 LEP 3-adrenergic rec 8p21 9p24 Frataxin 9q21 10p14 10q25 Insulin 11p13 KIR6.2 Sulf. receptor 12q15 HNF1a 12q24 IPF1 IRS2 14q31 16p12 Rad 17p12 HNF1b SERCA3 Glucagon receptor 18q11 Insulin receptor GIP receptor Glycogen synthase 20p12 HNF4a 20q12-13 Xq23 A3243G LOD 3.6 2 LOD<3.6 21
Diabetes-susceptibility QTLs Chr1 Chr2 Chr5 Chr8 Chr14 Chr17 22
Islets in D/D animals are hypoplastic compared to islets in B/B animals B/B: D/D: 10x 4x Do beta cells in D/D animals replicate as well as beta cells in B/B animals? B/B: D/D: 60x 20x 23
Ll Ll In situ-stained zebrafish embryos Endoderm (foxa3-gfp) Control (buffer injected) 48 hpf (hours post fertilization) 12/12 single cluster cells Beta cells ( -insulin) Ll splice-site morpholino #1 48 hpf: Ll splice-site morpholino #2 48 hpf: 14/15 scattered cells 10/12 scattered cells Morpholino-mediated knock-down of mouse Ll ortholog in zebrafish results in a beta cell-specific defect 24
rat D1S1679 Cen to D1S1589 161.7 163.9 UK 177.7 French D1S2681D1S2658 D1S2818 155.3 156.9 158.6 D1S398 Amish D1S2844 149.7 APOA2? 1q21.3 Obq9 (obesity QTL): NZO x SM cross D1S2858 Utah?155.4 156.9 163.2 CRP D1S196 APOA2 Pima <45y 151.4 159.2 169.7 D1S303? D1Mit145 Columbia (D1Mit270) (D1Mit401) 146.5 GK152.6 157.4 162.3 ARNT NTRK1 DUSP12 GPA33 (D1Mit370) 146.5 160.3 PBX1 181.2 1q25 158 169.7 Framingham 198.9 D1S1677 mouse Chinese D1S1589 180.1 Pima <25y D1S2127 Region within GANESH (Genome Annotation Network for Expressed Sequence Hits) 140 150 160 170 180 190 Comprative mouse-human-rat map for human chr 1q23 indicating populations and locations of peak LOD scores in linkage scans for type 2 diabetes. D1S1678 200 human Scale: UCSC human browser (Nov02) (Mb) END 25