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胰岛素抵抗与多囊卵巢综合征北京大学深圳医院生殖医学中心李蓉1921年,Achard和Their首先发现糖代谢异常与高雄激素血症有关;1935年,SteinandLeventhal首先提出PCOS;1976年,Kahn和同事发现高雄激素血症、胰岛素抵抗和黑棘皮症有关;1980年,Burghen首先提出PCOS与高雄激素血症、高胰岛素血症有关;背景Figure2.Sectionofapolycysticovarywithmultiplesubscapularfollicularcystsandstromalhypertrophy(leftpanel).Athigherpower(x100)islandsofluteinizedthecacellsarevisibleinthestroma(rightpanel).Thismorphologicalchangeiscalledstromalhyperthecosisandappearstobedirectlycorrelatedwithcirculatinginsulinlevels.一、胰岛素与卵巢功能的关系胰岛素通过IGF-1受体刺激卵巢分泌雌激素,雄激素及孕酮(细胞色素p-450c17α17α-羟化酶)胰岛素抑制肝脏分泌SHBG雄激素的效应胰岛素抑制肝脏合成IGFBP-1IGF-1的效应同Gn相互作用抑制卵泡的凋亡闭锁上调IGF-1受体Figure1.PossibleMechanismsofInsulinStimulationofOvarianCytochromeP450c17ActivityandAndrogenproduction.Inthecacells,insulinmaydirectlystimulate(plussigns)ovariancytochromeP450c17,resultinginincreased17-hydroxylaseand,toalesserextent,17,20-lyaseactivity.Thiswouldleadtoincreasedproductionofandrostenedione,whichisthenconvertedtotestosteronebytheenzyme17-reductase.Alternativelyorinconjunctionwiththis,insulinmaystimulateovarianandrogenproductionindirectlybyenhancingtheamplitudeofserumluteinizinghormone(LH)pulses,andluteinizinghormonemaythenstimulateovariancytochromeP450c17activity.二、胰岛素抵抗与PCOS胰岛素及其受体的结构胰岛素是胰腺Langerhans小岛上的β-细胞产生多肽,由A链(21AAs)和B链(30AAs)构成。胰岛素受体由两个α-亚单位(135kDa)和两个β-亚单位(95kDa)构成的异构四聚体。α-亚单位:存在于细胞膜外,富含半胱氨酸,是胰岛素的结合位点;β-亚单位:三种类型:细胞膜外、细胞膜、细胞浆内,后者含有ATP结合位点和几个酪氨酸自动磷酸化位点。胰岛素的作用机理(1)胰岛素受体β-亚单位的酪氨酸位点磷酸化胰岛素胰岛素受体α-亚单位获得激酶活性,细胞内蛋白磷酸化胰岛素受体底物(IRS)突变胰岛素抵抗基因OGTTPCOS高胰岛素血症FIG1.TheIRisaheterotetramerconsistingoftwoa,b-dimerslinkedbydisulfidebonds.Thea-subunitcontainstheligand-bindingsite,andtheb-subunitcontainsaligand-activatedtyrosinekinase.Tyrosineautophosphorylationincreasesthereceptor’styrosinekinaseactivitywhereasserinephosphorylationinhibitsit.胰岛素的作用机理(2)胰岛素抵抗的机理(1)受体与胰岛素的结合或者受体亲和力无改变50%PCOS-ser:IR酪氨酸磷酸化或IR丝氨酸磷酸化50%PCOS-nl:IR下游信号传导受阻(IRS-1的磷酸化;PI3-K的活性)Figure9.Thetyrosine-phosphorylatedIRphosphorylatesintracellularsubstrates,suchasIRsubstrate(IRS)-1andIRS-2,initiatingsignaltransductionandtheplieotropicactionsofinsulin.TheactivationofPI3-K(PI3-kinase)bytyrosine-phosphorylatedIRS-1appearstobethepathwayforinsulin-mediatedglucosetransport.TheRas-MAPkinasepathwayappearstoregulatecellgrowthandglycogensynthesis.胰岛素抵抗的机理(2)IR丝氨酸磷酸化因子IR酪氨酸激酶抑制因子膜糖蛋白PC-1/TNF-a胰岛素抵抗的机理(3)抑制IR酪氨酸激酶活性Figure14.Insulinresistancein50%ofPCOSwomenappearstobesecondarytoacellmembrane-associatedfactor,presumablyaserine/threoninekinase,thatserine-phosphorylatestheIR-inhibitingsignaling.SerinephosphorylationofIRS-1appearstobethemechanismforTNF-mediatedinsulinresistance.ThemembraneglycoproteinPC-1alsoinhibitsIRkinaseactivity,butitdoesnotcauseserinephosphorylationofthereceptor.Theseareexamplesofarecentlyappreciatedmechanismforinsulinresistancesecondarytofactorsregulatingthereceptor’styrosinekinaseactivity.胰岛素抵抗的机理(4)FIG.2.anormal(control),aPCOSwomanwithnormalinsulin-stimulatedtyrosinephosphorylation(PCOS-nl)andaPCOSwomanwithhighbasalautophosphorylationonserineresidues(PCOS-ser);S-serine,Y-tyrosine.Basalautophosphorylationisincreasedandthereisminimalfurtherinsulin-stimulatedphosphorylationinthePCOS-serb-subunits.Thehighbasalphosphorylationrepresentsphosphoserine,andphosphotyrosinecontentdoesnotincreaseinresponsetoinsulininthePCOS-serb-subunits.FIG.3.astrikingincreaseinphosphoserinecontentandamarkeddecreaseininsulin-stimulatedphosphotyrosinecontentaftermixinghIRwithPCOS-serlectineluatesascomparedwithmixinghIRwithcontrollectineluatesorintheabsenceofmixing.NIDDMIR数目/IR磷酸化/葡萄糖转运胰岛素刺激的肌糖原合成高血糖症代偿PCOS与NIDDM的关系(1)PCOSIR传导信号起始阶段异常IR磷酸化独特类型PCOS-相关的胰岛素抵抗与其它NIDDM基因相区别PCOS与NIDDM的关系(2)PCOS是NIDDM的一个独特的亚型对患有PCOS的绝经后妇女,PCOS及葡萄糖不耐受的研究显示PCOS-相关的胰岛素抵抗使患NIDDM的危险显著增加。降低雄激素水平不能完全恢复胰岛素敏感性。雄激素不引起或引起轻度胰岛素抵抗。雄激素能引起胰岛素抵抗?高胰岛素血症能引起高雄激素血症?在PCOS病人,高胰岛素血症能增加雄激素水平。胰岛素通过IR直接介导,而不是占据了IGF-I受体。类固醇合成异常。降低胰岛素水平却未改变高雄激素的异常。FIG.6AsinglefactorthatcausesserinephosphorylationoftheIRandserinephosphorylationofP450c17,thekeyregulatoryenzymecontrollingandrogenbiosynthesis,couldproduceboththeinsulinresistanceandthehyperandrogenismcharacteristicofPCOS.Itisalsopossiblethattheinsulinresistanceandthereproductiveabnormalitiesreflectseparategeneticdefectsandthattheinsulinresistanceunmasksthesyndromeingeneticallysusceptiblewomen.RecentstudiessuggestthatinsulinactingthroughitsownreceptoraugmentssteroidogenesisandLHrelease.Androgensamplifytheassociatedinsulinresistance.三、PCOS的诊断PCOS的定义(1)(1990年NIH标准)慢性无排卵(Chronicanovalation)高雄激素血症(Hyperandrogenism)(临床或生化)(clinicalorbiochemical)排除其他代谢异常(Exclusionofotheretiologies)PCOS的定义(2)(2003年标准)少或无排卵(Oligoand/oranovulation)高雄激素血症(Hyperandrogenism)(clinicaland/orbiochemical)多囊卵巢(Polycysticovaries)(2outof3criteria)排除其他代谢异常(Exclusionofotheretiologies)PCOS的定义(3)高雄激素血症(Hyperandrogenism)卵巢功能异常(Ovulatorydysfunction)排除其他代谢异常(Theexclusionofspecificdisorders)PCO不是必需的诊断要求LH/FSH比值也不是必需的诊断要求胰岛素抵抗的诊断餐后2小时胰岛素水平>100μU/mlGLU/INS>4.5INS/GLU<0.3重叠临床检测与胰岛素水平并不完全相关所有的PCOS病人所有的肥胖妇女四、胰岛素抵抗的处理双胍类药物二甲双胍(如格华止)血管紧张素转换酶抑制剂(如开博通、蒙诺)胰岛素增敏剂(如罗格列酮)饮食和运动降低胰岛素抵抗的方法饮食和运动疗法限制热量或减轻
本文标题:胰岛素抵抗与多囊卵巢综合征解析
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