Type2diabetesDerekLeRoithType2diabetesDerekLeRoith1InsulinResistance:ACoreDefectofTheMetabolicSyndromeInsulinResistanceDyslipidemiaObesityHypertensionDysfibrinolysisHyperglycemiaEndothelialDysfunctionMacrovascularDiseaseGlucoseIntoleranceAdaptedfromMcFarlaneSI,etal.JClinEndocrinolMetab.2001;86:713-718;ReuschJEB.AmJCardiol.2002;90(suppl):19G-26G.InsulinResistance:ACoreDef2ChrisRhodesPh.D.PNRI,Seattle,WA.01020FastingGlucose(mM/L)0200400FastingInsulin(pmol/L)05001000PlasmaFFA(μmol/L)50100150?-CellMass(%change)02.55AmyloidDeposit(%PancreaticArea)INCREASINGAGEAND/0RDEGREEOFOBESITY(increasingperipheralinsulinresistance)FastingPlasmaGlucoseFastingSerumInsulinCirculatingFFAPancreatic?-CellMassIsletAmyloidDepositNormalAdaptationGlucoseIntolerantType-2DiabetesThePathogenesisofObesity-linkedType-2Diabetes[TIMM(2002)8:375-384]ChrisRhodesPh.D.01020Fasting3ChrisRhodesPh.D.PNRI,Seattle,WA.Type-2Diabetes-AQuestionofBalancePERIPHERALINSULINRESISTANCE?-CELLMASS&FUNCTIONNon-DiabeticStatePERIPHERALINSULINRESISTANCE?-CELLMASS&FUNCTIONDiabeticStateChrisRhodesPh.D.Type-2Diab4RegulationofIslet-CellMassandFunctionRegulationofIslet-CellMas5MechanismsofcellfailureinT2DChristopherJ.NolanMechanismsofcellfailurei6MechanismsofcellcompensationforinsulinresistanceChristopherJ.NolanMechanismsofcellcompensat7CellCompensation:ChristopherJ.NolanExpansionofcellmassEnhancedinsulinbiosynthesisIncreasedresponsivenessofnutrient-secretioncouplingCellCompensation:Christophe8ChristopherJ.NolanExpansionofCellMassGlucoseFFAGLP-1ChristopherJ.NolanExpansion9EnhancedInsulinBiosynthesisEnhancedInsulinBiosynthesis10IncreasedResponsivenessIncreasedResponsivenes1116博士研究課——生命科學前沿進展——糖尿病魏熾炬4課件1216博士研究課——生命科學前沿進展——糖尿病魏熾炬4課件13BiphasicInsulinSecretionBiphasicInsulinSecretion14GlucoseIns/IGFAcetylcholineKristinaM.UtzschneiderGlucoseIns/IGFAcetylcholineKri15ChristopherJ.NolanSusceptibleCellsGeneticandacquireddefects:Glucolipo-detoxificationMitochondrialfunctionAnaplerosis/cataplerosisAMPK/Mal-CoATG/FFAcyclingInsulinbiosynthesisCouplingmechanismsExocytosisIntrauterinefactorsChristopherJ.NolanSusceptibl16I.E.T.vandenBergDiacylglycerolTriglyceridesFattyAcidsAcylatedProteinsKATP-independentInsulinSecretioncarnitinepalmitoyltransferase-1(CPT1)I.E.T.vandenBergDiacylglyc17AMPK/Malonyl-CoASignalingNetworkAMPK/Malonyl-CoASignalingNet18TG/FFACyclinginBetaCellsTG/FFACyclinginBetaCells19IntraUterineGrowthRetardation(IUGR)REBECCAA.SIMMONSIUGRIntraUterineGrowthRetardatio20ChristopherJ.NolanCellsdysfunctionIGTandearlyT2DT2D:initiationrolesGluolipotoxicityLipotoxicityOxidativestress/ROSDysregulatedTG/FFAcyclingAlteredAMPK/Mal-CoACellexhaustionERstressChristopherJ.NolanCellsdy21LipotoxicityLipotoxicity22GlucolipotoxicityinBetaCellsMarcPrentkiGlucolipotoxicityinBetaCell23F.M.AshcroftNicotinamidenucleotidetranshydrogenase:alinkbetweeninsulinsecretion,glucosemetabolismandoxidativestressF.M.AshcroftNicotinamidenucl24ChristopherJ.NolanCellfailureOvertandlateT2DT2D:progressionrolesGluolipotoxicityGlucotoxicityOxidativestress/ROSIsletinflammationProteinO-glycosylationAGEsDedifferentiationAmyloiddepositionApoptosisChristopherJ.NolanCel25MichaelBrownleeFourPathwaysofHyperglycaemicDamageMichaelBrownleeFourPathways26MichaelBrownleeAldoseReductaseandThePolyolPathwayDecreasedlevelsofGSHIncreasedoxidativestressMichaelBrownleeAldoseReducta27MichaelBrownleeProductionofAdvancedGlycationEnd-Product(AGE)PrecursorsMichaelBrownleeProductionof28MichaelBrownleeConsequencesofHyperglycaemia-InducedActivationofProteinKinaseC(PKC)MichaelBrownleeConsequenceso29MichaelBrownleeTheHexosaminePathwayMichaelBrownleeTheHexosamine30Type2diabetesDerekLeRoithType2diabetesDerekLeRoith31InsulinResistance:ACoreDefectofTheMetabolicSyndromeInsulinResistanceDyslipidemiaObesityHypertensionDysfibrinolysisHyperglycemiaEndothelialDysfunctionMacrovascularDiseaseGlucoseIntoleranceAdaptedfromMcFarlaneSI,etal.JClinEndocrinolMetab.2001;86:713-718;ReuschJEB.AmJCardiol.2002;90(suppl):19G-26G.InsulinResistance:ACoreDef32ChrisRhodesPh.D.PNRI,Seattle,WA.01020FastingGlucose(mM/L)0200400FastingInsulin(pmol/L)05001000PlasmaFFA(μmol/L)50100150?-CellMass(%change)02.55AmyloidDeposit(%PancreaticArea)INCREASINGAGEAND/0RDEGREEOFOBESITY(increasingperipheralinsulinresistance)FastingPlasmaGlucoseFastingSerumInsulinCirculatingFFAPancreatic?-CellMassIsletAmyloidDepositNormalAdaptationGlucoseIntolerantType-2DiabetesThePathogenesisofObesity-linkedType-2Diabetes[TIMM(2002)8:375-384]ChrisRhodesPh.D.01020Fasting33ChrisRhodesPh.D.PNRI,Seattle,WA.Type-2Diabetes-AQuestionofBalancePERIPHERALINSULINRESISTANCE?-CELLMASS&FUNCTIONNon-DiabeticStatePERIPHERALINSULINRESISTANCE?-CELLMASS&FUNCTIONDiabeticStateChrisRhodesPh.D.Type-2Diab34RegulationofIslet-CellMassandFunctionRegulationofIslet-CellMas35MechanismsofcellfailureinT2DChristopherJ.NolanMechanismsofcellfailurei36MechanismsofcellcompensationforinsulinresistanceChristopherJ.NolanMechanismsofcellcompensat37CellCompensation:ChristopherJ.NolanExpansionofcellmassEnhancedinsulinbiosynthesisIncreasedresponsivenessofnutrient-secretioncouplingCellCompensation:Christophe38ChristopherJ.NolanExpansionofCellMassGlucoseFFAGLP-1ChristopherJ.NolanExpansion39EnhancedInsulinBiosynthesisEnhancedInsulinBiosynthesis40IncreasedResponsivenessIncreasedResponsivenes4116博士研究課——生命科學前沿進展——糖尿病魏熾炬4課件4216博士研究課——生命科學前沿進展——糖尿病魏熾炬4課件43BiphasicInsulinSecretionBiphasicInsulinSecretion44GlucoseIns/IGFAcetylcholineKristinaM.UtzschneiderGlucoseIns/IGFAcetylcholineKri45ChristopherJ.NolanSusceptibleCellsGeneticandacquireddefects:Glucolipo-detoxificationMitochondrialfunctionAnaplerosis/cataplerosisAMPK/Mal-CoATG/FFAcyclingInsulinbiosynthesisCouplingmechanismsExocytosisIntrauterinefactorsChristopherJ.NolanSusceptibl46I.E.T.vandenBergDiacylglycerolTriglyceridesFattyAcidsAcylatedProteinsKATP-independentInsulinSecretioncarnitinepalmitoyltransferase-1(CPT1)I.E.T.vandenBergDiacylglyc47AMPK/Malonyl-CoASignalingNetworkAMPK/Malonyl-CoASignalingNet48TG/FFACyclinginBetaCellsTG/FFACyclinginBetaCells49IntraUterineGrowthRetardation(IUGR)REBECCAA.SIMMONSIUGRIntraUterineGrowthRetardatio50ChristopherJ.NolanCellsdysfunctionIGTandearlyT2DT2D:initiationrolesGluolipotoxicityLipotoxicityOxidativestress/ROSDysregulatedTG/FFAcyclingAlteredAMPK/Mal-CoACellexhaustionERstressChristopherJ.NolanCellsdy51LipotoxicityLipotoxicity52GlucolipotoxicityinBetaCellsMarcPrentkiGlucolipotoxicityinBetaCell53F.M.AshcroftNicotinamidenucleotidetranshydrogenase:alinkbetweeninsulinsecretion,glucosemetabolismandoxidativestressF.