Transcription
Pathophysiology of type 2 diabetes mellitusR. LeibelNaomi Berrie Diabetes Center25 February 2008Body Mass Index Chart25-29.9 overweight; 30-39.9 obese; 40 extreme obesityWeight (lbs)120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 3005'0"5'2"5'4"Height5'6"5'8"5'10"6'0"6'2"6'4"1
Prevalence of Obesity and Diagnosed Diabetes Among US Adults, 1991 and20011986 - 2000. BMI 30 2x; 40 4x; 50 6x.Mokdad, A. H. et al. JAMA 2003;289:76-79Relative Risk of Type 2 Diabetes inUS Women According to BMIRelative risk(age-adjusted)100806040200Bars represent 95%confidence intervals .0–28.929.0–30.931.0–32.933.0– ³35.034.9BMI (kg/m2)Data derived from Colditz et al. Ann Intern Med. 1995;122:481-7.2
Plasma Glucose and Insulin ProfilesAfter Oral Glucose ChallengeReaven GM et al. Diabetologia. 1977;13:201-206.3
Close this window to return to the previous window4Nature Ma
Millions of Cases of Diabetes in 2000 and Projections for 2030, with Projected Percent ChangesHossain P et al. N Engl J Med 2007;356:213-2155
Clinical definition of diabetesPlasma glucose 200 mg/dl at any timeorFasting (post-absorptive) plasmaglucose 125 mg/dlor2 hour post-75gm oral glucose load plasmaglucose 200 mg/dlDiab. Care; 23:381, 20006
Clinical Definition Impaired GlucoseToleranceFasting (post-absorptive) plasma glucose: 100-125 mg/dlor2 hr (OGTT) plasma glucose: 140 - 199 mg/dlDiab. Care; 23:381, 2000Predisposing Genes& update 4 04Predisposing GenesPredisposing EnvironmentObesityType 2 Diabetes80% diabetic are obese50 % obese are diabetic7
Close this window to return to the previous windowFigure 1Note: Figures may be difficult to render in a web browser.In such cases, we recommend downloading the PDFversion of this document.Nature MacmillanPublishersLtdNote: Figures may be difficult to render in a web browser.8
In the absence of insulin, GLUT4 is localized to an intracellular compartmentGLUT1MembraneGLUT1GLUT4NucleusIn the presence of insulin, GLUT4 translocates to the plasma membraneGLUT4GLUT1MembraneIRSPI 3-KPKCAKTTranslocation?GLUT4Nucleus9
Note: Figures may be difficult to render in a web browser.In such cases, we recommend downloading the PDFversion of this document.Nature nd.10
Obici et al. Nature Medicine. 8:1396, 2002Potential rate-controlling steps in insulin-mediated muscle glycogensynthesis11
Mechanisms FFA-induced insulin resistance in skeletal muscleRandleShulmanAdipose tissue is an endocrine organ.Lean adiposetissueMuscleacrp30acrp30TNFαObese adiposetissueLiverTNFαIL-6IL-6leptinBrainleptin12
In obese mice, adipose tissue macrophageshave an unusual morphology: lipidvacuoles, multinucleated.Lean 16week BL6female,omental fatob/ob 16week BL6female,omental fatWeisberg et al., JCI, Dec 2003Adipose tissue macrophagesPerigonadal:r2 0.7, P 10–4Perirenal:r2 0.7, P 10–4Mesenteric:r2 0.9, P 10–4Subcutaneous:r2 0.39, P 0.01Weisberg et al., JCI, Dec 200313
Improved insulin sensitivity in Ccr2-/miceInsulin tolerance test Ccr2 / with dietaryobesity; 44% body fatGlucose tolerance test Ccr2 -/- with dietaryobesity; 45% body fat14
15
Prospective Analysis8 Year Cumulative Incidence (%) of Type 2Diabetes in Pima Indians317 NGT/62 betes Prevalence (%) in Offspring byMother’s Diabetes at Diabetic5-910-1415-1920-2425-29Age (years)16
Kahn SE et al. Nature 2006Longitudinal Study of the Transitionfrom NGT to Type 2 DiabetesEarly Insulin Response vs Insulin ActionAIR (uU/ml)400NGT NGT300N 31NGTNGT200IGTN 17100DIA001234M-low (mg/kg-EMBS/min)Adapted from Weyer et al, 199917
18
Close this window to return to the previous windowDPPTNature nd.19
Percentage of Weight Loss Achieved Over the 2-Year Study Period (n 60) and IndividualWeight Measures at Baseline and at 2 YearsDixon, J. B. et al. JAMA 2008;299:316-323.Copyright restrictions mayapply.20
21
Kahn SE et al. Nature 200622
Diabetes-susceptibility QTLsChr1Chr2Chr5Chr8Chr14Chr1723
Do beta cells in D/D animals replicate aswell as beta cells in B/B animals?B/B:D/D:60x20x24
Zebrafishprior candidatesTCF2, SLC30A8 not on this affy arrayFrayling. Nature Reviews. Genetics. 8:657, 2007 from Zeggini et al. Science. 316:1336, 200725
Cauchi S et al. Journal of Molecular Medicine 2007[11C] DTBZ and PET visualizes thehuman pancreas26
END27
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 5'4" Height Weight (lbs) 5'2" 5'0" 5'10" 5'8" 5'6" 6'0" 6'2" 120 130 140 150 160 170
