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1、脂中毒與胰島素抵抗新概念李秀鈞華西醫(yī)科大學(xué)附一院內(nèi)分泌科Productsofadipocyteswhichmayberelevanttothepathophysiologyofthemetabolicsyndrome脂肪組織——新的內(nèi)分泌器官Resistin(2001)Adiponectin(1991)Vitronectin(2000)PPARsOmentin(2003)病因/機(jī)理遺傳因素環(huán)境因素AC肥大/增殖AdipocytokinesTNF-α↑NEFA↑IL-6↑Resistin↑PAI-1↑AP↓VF(omentalF)↓apM1OmentinMSIRI
2、GT高血壓血脂異常DC,2003,26:2442AC/IR新概念A(yù)C致mIRAC致LIRAC致心肌IRAC致胰IRAC致內(nèi)皮IRAC致AC自身IRTNF-α妨礙肌、脂Ins信號(hào)轉(zhuǎn)導(dǎo)Glut4表達(dá)、轉(zhuǎn)位↓肌、脂G攝取↓糖原合成↓↑脂解，↑NEFAAdipostat，TNF-α/leptin,限制AC體積增大促進(jìn)細(xì)胞調(diào)亡，腫瘤惡病質(zhì)有關(guān)↑IL-6IL-6，（來(lái)源MP，LC，AC）ThemostendocrineCKTNF-α↑CRPOB-lowgradeinflammatorystate→AsHPAAXIS↑ACIL-6↑（一）F脂肝、脂腦對(duì)話↑肝TG↑脂解OPE2
3、（—）（—）Resistin(2001)Ch19（人）僅于WAT特異表達(dá)抗resistin-Ab處理，In-Med-G攝取↑,BG↓TZD（PPAR-γ配基）下調(diào)resistin肥胖——Resistin——DM2SI↓IGTDM2肥胖——Resistin——DM2SI↓IGTDM2PPAR-γTZDLinkbtwob&DM2網(wǎng)膜素——又一新發(fā)現(xiàn)的脂肪激素(2003)313A.A作用：促進(jìn)ACIns介導(dǎo)的G運(yùn)轉(zhuǎn)↑Akt/PKB調(diào)節(jié)能量代謝及胰島素信號(hào)Ibid200352(s1):A1NEFA-信號(hào)分子FAG↓Glut4↓mHGP/HPO↑In↓LB.cE.cNO↓
4、，血管舒張↓EctopicdepositionoflipidsNEFA-OX↓→FFA→Reesterification→non-ACmLβ、cE.cIRβ、cFASpilloverLipotoxicityofnon-oxmetabolicpathwayLeptinresistance對(duì)β、c保護(hù)作用↓↑FattyAcylcoATGMembraneDisruption(Detergent)Ceramide↓iNOS↓ApoptosisLipidPeroxidationβ、cFASpilloverLipotoxicityofnon-oxmetabolicpathw
5、ayLeptinresistance對(duì)β、c保護(hù)作用↓↑FattyAcylcoA↑TGMembraneDisruption(Detergent)Ceramide↓iNOS↓ApoptosisLipidPeroxidationTZDAdiponectinmutationandmultimerizationArg112cysIle164ThrTrimerGly84ArgGly90Sermultimer↓AdiponectinDMWakiH,etal,Diabetes,2003,52(s1):A1APM13q27(Acrp30)(分化AC特異表達(dá))↑FFAoX↓BG↓
6、MS↓DM↓obAPM13q27（單信型Promotor/Exon單核苷多態(tài)性）MS（IR）DM2↓ObFroguelP.DGAT2-5Leptin抵抗IRS2Ob，LP抵抗，AC肥大DGAT2Gene上調(diào)WATDGAT1Gene下調(diào)WATDGAT2Gene表達(dá)↑LP↓AC肥大通過(guò)兩條途徑肥胖DM2相關(guān)的機(jī)理AC→AdipocytokinesIR→糖、脂代謝異常β、c功能障礙IGT→DM2糖尿病脂代謝異常FFA-Ox↓Non-Ox↑M↑Β-cell↑L↑（NonAcfatcontent↑）（ectopicdepositionoffat）Lipotoxicityh
7、ypothesis肥胖糖尿病β細(xì)胞脂中毒→DMPre-ObPeriod<5wkObZDF胰島結(jié)構(gòu)、功能正常ObPre-DM(7-9WK),胰島增生，βC團(tuán)↑4x高胰島素血癥DM（10-12WK)TG積聚↑-50X（達(dá)峰）βC死亡，βC團(tuán)顯著↓βC功能大減，DM發(fā)生UngerRH,etal,Diabets,2001,50:S118J.DenisMcGarry,PhDChristopherB.Newgard,PhD脂代謝異?？赡転镈M2的主要或原發(fā)事件為DM2的基本的病理生理變化DiabesityDiabetesMellipitusDMZimmet,McGarry,
8、Newgard針對(duì)糖脂中
