16-博士研究课-生命科学前沿进展-糖尿病-魏炽炬-4课件

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)50100150ß-CellMass(%change)02.55AmyloidDeposit(%PancreaticArea)INCREASINGAGEAND/0RDEGREEOFOBESITY(increasingperipheralinsulinresistance)FastingPlasmaGlucoseFastingSerumInsulinCirculatingFFAPancreaticß-CellMassIsletAmyloidDepositNormalAdaptationGlucoseIntolerantType-2DiabetesThePathogenesisofObesity-linkedType-2Diabetes[TIMM(2002)8:375-384]ChrisRhodesPh.D.01020Fasting3ChrisRhodesPh.D.PNRI,Seattle,WA.Type-2Diabetes-AQuestionofBalancePERIPHERALINSULINRESISTANCEß-CELLMASS&FUNCTIONNon-DiabeticStatePERIPHERALINSULINRESISTANCEß-CELLMASS&FUNCTIONDiabeticStateChrisRhodesPh.D.Type-2Diab4RegulationofIslet-CellMassandFunctionRegulationofIslet-CellMas5Mechanismsof

cellfailureinT2DChristopherJ.NolanMechanismsofcellfailurei6Mechanismsof

cellcompensationforinsulinresistanceChristopherJ.NolanMechanismsofcellcompensat7

CellCompensation:ChristopherJ.NolanExpansionof

cellmassEnhancedinsulinbiosynthesisIncreasedresponsivenessofnutrient-secretioncouplingCellCompensation:Christophe8ChristopherJ.NolanExpansionof

CellMassGlucoseFFAGLP-1ChristopherJ.NolanExpansion9EnhancedInsulinBiosynthesisEnhancedInsulinBiosynthesis10IncreasedResponsivenessIncreasedResponsivenes1116-博士研究课——生命科学前沿进展——糖尿病-魏炽炬-4课件1216-博士研究课——生命科学前沿进展——糖尿病-魏炽炬-4课件13BiphasicInsulinSecretionBiphasicInsulinSecretion14GlucoseIns/IGFAcetylcholineKristinaM.UtzschneiderGlucoseIns/IGFAcetylcholineKri15ChristopherJ.NolanSusceptible

CellsGeneticandacquireddefects: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.Nolan

CellsdysfunctionIGTandearlyT2DT2D:initiationrolesGluolipotoxicityLipotoxicityOxidativestress/ROSDysregulatedTG/FFAcyclingAlteredAMPK/Mal-CoA

CellexhaustionERstressChristopherJ.NolanCellsdy21LipotoxicityLipotoxicity22GlucolipotoxicityinBetaCellsMarcPrentkiGlucolipotoxicityinBetaCell23F.M.AshcroftNicotinamidenucleotidetranshydrogenase:alinkbetweeninsulinsecretion,glucosemetabolismandoxidativestressF.M.AshcroftNicotinamidenucl24ChristopherJ.Nolan

CellfailureOvertandlateT2DT2D:progressionrolesGluolipotoxicityGlucotoxicityOxidativestress/ROSIsletinflammationProteinO-glycosylationAGEsDedifferentiationAmyloiddepositionApoptosisChristopherJ.NolanCel25MichaelBrownleeFourPathwaysofHyperglycaemicDamageMichaelBrownleeFourPathways26MichaelBrownleeAldoseReductaseandThePolyolPathwayDecreasedlevelsofGSHIncreasedoxidativestressMichaelBrownleeAldoseReducta27MichaelBrownleeProductionofAdvancedGlycationEnd-Product(AGE)PrecursorsMichaelBrownleeProductio