16-博士研究课-生命科学前沿进展-糖尿病课件.ppt

1、Type 2 diabetesDerek LeRoithInsulin Resistance: A Core Defect of The Metabolic SyndromeInsulinResistanceDyslipidemiaObesityHypertensionDysfibrinolysisHyperglycemiaEndothelialDysfunctionMacrovascularDiseaseGlucoseIntoleranceAdapted from McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86:713-718; R

2、eusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.Chris Rhodes Ph.D.PNRI, Seattle, WA.01020Fasting Glucose (mM/L)0200400Fasting Insulin (pmol/L)05001000Plasma FFA( mol/L)50100150-Cell Mass (% change)02.55Amyloid Deposit (% Pancreatic Area)INCREASING AGE AND/0R DEGREE OF OBESITY(increasing peripheral i

3、nsulin resistance)Fasting Plasma GlucoseFasting Serum InsulinCirculating FFAPancreatic -Cell MassIslet Amyloid DepositNormalAdaptationGlucose IntolerantType-2 DiabetesThe Pathogenesis of Obesity-linked Type-2 DiabetesTIMM (2002) 8: 375-384Chris Rhodes Ph.D.PNRI, Seattle, WA.Type-2 Diabetes - A Quest

4、ion of Balance PERIPHERAL INSULINRESISTANCE-CELL MASS & FUNCTIONNon-Diabetic StatePERIPHERAL INSULINRESISTANCE-CELL MASS & FUNCTIONDiabetic StateRegulation of Islet -Cell Mass and FunctionMechanisms of cell failure in T2DChristopher J. NolanMechanisms of cell compensation for insulin resistanceChris

5、topher J. Nolan Cell Compensation:Christopher J. Nolan1. Expansion of cell mass 2. Enhanced insulin biosynthesis3. Increased responsiveness of nutrient-secretion couplingChristopher J. NolanExpansion of Cell Mass GlucoseFFAGLP-1Enhanced Insulin Biosynthesis Increased ResponsivenessBiphasic Insulin S

6、ecretionGlucoseIns/IGFAcetylcholineKristina M. UtzschneiderChristopher J. NolanSusceptible CellsGenetic and acquired defects:Glucolipo-detoxificationMitochondrial functionAnaplerosis/cataplerosisAMPK/Mal-CoATG/FFA cyclingInsulin biosynthesisCoupling mechanismsExocytosisIntrauterine factorsI. E.T. va

7、n den BergDiacylglycerol Triglycerides Fatty AcidsAcylated ProteinsKATP-independentInsulin Secretioncarnitine palmitoyltransferase-1 (CPT 1)AMPK/Malonyl-CoA Signaling NetworkTG/FFA Cycling in Beta CellsIntraUterine Growth Retardation (IUGR)REBECCA A. SIMMONSIUGRChristopher J. Nolan Cells dysfunction

8、IGT and early T2DT2D: initiation rolesGluolipotoxicityLipotoxicityOxidative stress/ROSDysregulated TG/FFA cyclingAltered AMPK/Mal-CoA Cell exhaustionER stressLipotoxicityGlucolipotoxicity in Beta CellsMarc PrentkiF.M. AshcroftNicotinamide nucleotide transhydrogenase: a link between insulin secretion

9、, glucose metabolism and oxidative stressChristopher J. Nolan Cell failureOvert and late T2DT2D: progression rolesGluolipotoxicityGlucotoxicityOxidative stress/ROSIslet inflammationProtein O-glycosylationAGEsDedifferentiationAmyloid depositionApoptosisMichael BrownleeFour Pathways of Hyperglycaemic

10、DamageMichael BrownleeAldose Reductase and The Polyol PathwayDecreased levels of GSHIncreased oxidative stressMichael BrownleeProduction of Advanced Glycation End-Product (AGE) PrecursorsMichael BrownleeConsequences of Hyperglycaemia-Induced Activation of Protein Kinase C (PKC)Michael BrownleeThe Hexosamine Pathway