脂肪与胰岛素抵抗新概念修改

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1、脂中毒与胰岛素抵抗新概念李秀钧华西医科大学附一院内分泌科Productsofadipocyteswhichmayberelevanttothepathophysiologyofthemetabolicsyndrome脂肪组织——新的内分泌器官Resistin(2001)Adiponectin(1991)Vitronectin(2000)PPARsOmentin(2003)病因/机理遗传因素环境因素AC肥大/增殖AdipocytokinesTNF-α↑NEFA↑IL-6↑Resistin↑PAI-1↑AP↓VF(omentalF)↓apM1OmentinMSIRI

2、GT高血压血脂异常DC,2003,26:2442AC/IR新概念AC致mIRAC致LIRAC致心肌IRAC致胰IRAC致内皮IRAC致AC自身IRTNF-α妨碍肌、脂Ins信号转导Glut4表达、转位↓肌、脂G摄取↓糖原合成↓↑脂解，↑NEFAAdipostat，TNF-α/leptin,限制AC体积增大促进细胞调亡，肿瘤恶病质有关↑IL-6IL-6，（来源MP，LC，AC）ThemostendocrineCKTNF-α↑CRPOB-lowgradeinflammatorystate→AsHPAAXIS↑ACIL-6↑（一）F脂肝、脂脑对话↑肝TG↑脂解OPE2

3、（—）（—）Resistin(2001)Ch19（人）仅于WAT特异表达抗resistin-Ab处理，In-Med-G摄取↑,BG↓TZD（PPAR-γ配基）下调resistin肥胖——Resistin——DM2SI↓IGTDM2肥胖——Resistin——DM2SI↓IGTDM2PPAR-γTZDLinkbtwob&DM2网膜素——又一新发现的脂肪激素(2003)313A.A作用：促进ACIns介导的G运转↑Akt/PKB调节能量代谢及胰岛素信号Ibid200352(s1):A1NEFA-信号分子FAG↓Glut4↓mHGP/HPO↑In↓LB.cE.cNO↓

4、，血管舒张↓EctopicdepositionoflipidsNEFA-OX↓→FFA→Reesterification→non-ACmLβ、cE.cIRβ、cFASpilloverLipotoxicityofnon-oxmetabolicpathwayLeptinresistance对β、c保护作用↓↑FattyAcylcoATGMembraneDisruption(Detergent)Ceramide↓iNOS↓ApoptosisLipidPeroxidationβ、cFASpilloverLipotoxicityofnon-oxmetabolicpathw

5、ayLeptinresistance对β、c保护作用↓↑FattyAcylcoA↑TGMembraneDisruption(Detergent)Ceramide↓iNOS↓ApoptosisLipidPeroxidationTZDAdiponectinmutationandmultimerizationArg112cysIle164ThrTrimerGly84ArgGly90Sermultimer↓AdiponectinDMWakiH,etal,Diabetes,2003,52(s1):A1APM13q27(Acrp30)(分化AC特异表达)↑FFAoX↓BG↓

6、MS↓DM↓obAPM13q27（单信型Promotor/Exon单核苷多态性）MS（IR）DM2↓ObFroguelP.DGAT2-5Leptin抵抗IRS2Ob，LP抵抗，AC肥大DGAT2Gene上调WATDGAT1Gene下调WATDGAT2Gene表达↑LP↓AC肥大通过两条途径肥胖DM2相关的机理AC→AdipocytokinesIR→糖、脂代谢异常β、c功能障碍IGT→DM2糖尿病脂代谢异常FFA-Ox↓Non-Ox↑M↑Β-cell↑L↑（NonAcfatcontent↑）（ectopicdepositionoffat）Lipotoxicityh

7、ypothesis肥胖糖尿病β细胞脂中毒→DMPre-ObPeriod<5wkObZDF胰岛结构、功能正常ObPre-DM(7-9WK),胰岛增生，βC团↑4x高胰岛素血症DM（10-12WK)TG积聚↑-50X（达峰）βC死亡，βC团显著↓βC功能大减，DM发生UngerRH,etal,Diabets,2001,50:S118J.DenisMcGarry,PhDChristopherB.Newgard,PhD脂代谢异常可能为DM2的主要或原发事件为DM2的基本的病理生理变化DiabesityDiabetesMellipitusDMZimmet,McGarry,

8、Newgard针对糖脂中