胰島素抵抗與多囊卵巢綜合征

（優(yōu)選）胰島素抵抗與多囊卵巢綜合征當前1頁，總共31頁。Figure2.Sectionofapolycysticovarywithmultiplesubscapularfollicularcystsandstromalhypertrophy(leftpanel).Athigherpower(x100)islandsofluteinizedthecacellsarevisibleinthestroma(rightpanel).Thismorphologicalchangeiscalledstromalhyperthecosisandappearstobedirectlycorrelatedwithcirculatinginsulinlevels.當前2頁，總共31頁。一、胰島素與卵巢功能的關(guān)系當前3頁，總共31頁。胰島素通過IGF-1受體刺激卵巢分泌雌激素，雄激素及孕酮(細胞色素p-450c17α17α-羥化酶)胰島素抑制肝臟分泌SHBG雄激素的效應(yīng)胰島素抑制肝臟合成IGFBP-1IGF-1的效應(yīng)同Gn相互作用抑制卵泡的凋亡閉鎖上調(diào)IGF-1受體當前4頁，總共31頁。Figure1.PossibleMechanismsofInsulinStimulationofOvarianCytochromeP450c17ActivityandAndrogenproduction.Inthecacells,insulinmaydirectlystimulate(plussigns)ovariancytochromeP450c17,resultinginincreased17-hydroxylaseand,toalesserextent,17,20-lyaseactivity.Thiswouldleadtoincreasedproductionofandrostenedione,whichisthenconvertedtotestosteronebytheenzyme17-reductase.Alternativelyorinconjunctionwiththis,insulinmaystimulateovarianandrogenproductionindirectlybyenhancingtheamplitudeofserumluteinizinghormone(LH)pulses,andluteinizinghormonemaythenstimulateovariancytochrome

P450c17activity.當前5頁，總共31頁。二、胰島素抵抗與PCOS當前6頁，總共31頁。胰島素及其受體的結(jié)構(gòu)胰島素是胰腺Langerhans小島上的β-細胞產(chǎn)生多肽，由A鏈(21AAs)和B鏈(30AAs)構(gòu)成。胰島素受體由兩個α-亞單位（135kDa）和兩個β-亞單位(95kDa)構(gòu)成的異構(gòu)四聚體。

α-亞單位：存在于細胞膜外，富含半胱氨酸，是胰島素的結(jié)合位點；

β-亞單位：三種類型：細胞膜外、細胞膜、細胞漿內(nèi)，后者含有ATP結(jié)合位點和幾個酪氨酸自動磷酸化位點。當前7頁，總共31頁。胰島素的作用機理（1）胰島素受體β-亞單位的酪氨酸位點磷酸化胰島素胰島素受體α-亞單位獲得激酶活性，細胞內(nèi)蛋白磷酸化胰島素受體底物（IRS）突變胰島素抵抗基因OGTTPCOS高胰島素血癥當前8頁，總共31頁。FIG1.TheIRisaheterotetramerconsistingoftwoa,b-dimerslinkedbydisulfidebonds.Thea-subunitcontainstheligand-bindingsite,andtheb-subunitcontainsaligand-activatedtyrosinekinase.Tyrosineautophosphorylationincreasesthereceptor’styrosinekinaseactivitywhereasserinephosphorylationinhibitsit.胰島素的作用機理（2）當前9頁，總共31頁。胰島素抵抗的機理(1)受體與胰島素的結(jié)合或者受體親和力無改變50%PCOS-ser:IR酪氨酸磷酸化或IR絲氨酸磷酸化50%PCOS-nl:IR下游信號傳導受阻(IRS-1的磷酸化；PI3-K的活性）當前10頁，總共31頁。Figure9.Thetyrosine-phosphorylatedIRphosphorylatesintracellularsubstrates,suchasIRsubstrate(IRS)-1andIRS-2,initiatingsignaltransductionandtheplieotropicactionsofinsulin.TheactivationofPI3-K(PI3-kinase)bytyrosine-phosphorylatedIRS-1appearstobethepathwayforinsulin-mediatedglucosetransport.TheRas-MAPkinasepathwayappearstoregulatecellgrowthandglycogensynthesis.胰島素抵抗的機理（2）當前11頁，總共31頁。IR絲氨酸磷酸化因子IR酪氨酸激酶抑制因子膜糖蛋白PC-1/TNF-a胰島素抵抗的機理（3）抑制IR酪氨酸激酶活性當前12頁，總共31頁。Figure14.Insulinresistancein50%ofPCOSwomenappearstobesecondarytoacellmembrane-associatedfactor,presumablyaserine/threoninekinase,thatserine-phosphorylatestheIR-inhibitingsignaling.SerinephosphorylationofIRS-1appearstobethemechanismforTNF-mediatedinsulinresistance.ThemembraneglycoproteinPC-1alsoinhibitsIRkinaseactivity,butitdoesnotcauseserinephosphorylationofthereceptor.Theseareexamplesofarecentlyappreciatedmechanismforinsulinresistancesecondarytofactorsregulatingthereceptor’styrosinekinaseactivity.胰島素抵抗的機理（4）當前13頁，總共31頁。FIG.2.anormal(control),aPCOSwomanwithnormalinsulin-stimulatedtyrosinephosphorylation(PCOS-nl)andaPCOSwomanwithhighbasalautophosphorylationonserineresidues(PCOS-ser);S-serine,Y-tyrosine.Basalautophosphorylationisincreasedandthereisminimalfurtherinsulin-stimulatedphosphorylationinthePCOS-serb-subunits.Thehighbasalphosphorylationrepresentsphosphoserine,andphosphotyrosinecontentdoesnotincreaseinresponsetoinsulininthePCOS-serb-subunits.當前14頁，總共31頁。FIG.3.astrikingincreaseinphosphoserinecontentandamarkeddecreaseininsulin-stimulatedphosphotyrosinecontentaftermixinghIRwithPCOS-serlectineluatesascomparedwithmixinghIRwithcontrollectineluatesorintheabsenceofmixing.當前15頁，總共31頁。NIDDMIR數(shù)目/IR磷酸化/葡萄糖轉(zhuǎn)運胰島素刺激的肌糖原合成高血糖癥代償PCOS與NIDDM的關(guān)系(1)當前16頁，總共31頁。PCOSIR傳導信號起始階段異常IR磷酸化獨特類型PCOS-相關(guān)的胰島素抵抗與其它NIDDM基因相區(qū)別PCOS與NIDDM的關(guān)系（2）當前17頁，總共31頁。PCOS是NIDDM的一個獨特的亞型對患有PCOS的絕經(jīng)后婦女，PCOS及葡萄糖不耐受的研究顯示PCOS-相關(guān)的胰島素抵抗使患NIDDM的危險顯著增加。當前18頁，總共31頁。

降低雄激素水平不能完全恢復胰島素敏感性。雄激素不引起或引起輕度胰島素抵抗。雄激素能引起胰島素抵抗?當前19頁，總共31頁。高胰島素血癥能引起高雄激素血癥？在PCOS病人，高胰島素血癥能增加雄激素水平。胰島素通過IR直接介導，而不是占據(jù)了IGF-I受體。類固醇合成異常。降低胰島素水平卻未改變高雄激素的異常。當前20頁，總共31頁。FIG.6AsinglefactorthatcausesserinephosphorylationoftheIRandserinephosphorylationofP450c17,thekeyregulatoryenzymecontrollingandrogenbiosynthesis,couldproduceboththeinsulinresistanceandthehyperandrogenismcharacteristicofPCOS.Itisalsopossiblethattheinsulinresistanceandthereproductiveabnormalitiesreflectseparategeneticdefectsandthattheinsulinresistanceunmasksthesyndromeingeneticallysusceptiblewomen.RecentstudiessuggestthatinsulinactingthroughitsownreceptoraugmentssteroidogenesisandLHrelease.Androgensamplifytheassociatedinsulinresistance.當前21頁，總共31頁。三、PCOS的診斷當前22頁，總共31頁。PCOS的定義(1)

（1990年NIH標準）慢性無排卵（Chronicanovalation）高雄激素血癥（Hyperandrogenism）（臨床或生化）(clinicalorbiochemical)排除其他代謝異常（Exclusionofotheretiologies）當前23頁，總共31頁。PCOS的定義(2)

（2003年標準）少或無排卵（Oligoand/oranovulation）高雄激素血癥（Hyperandrogenism）(clinicaland/orbiochemical)多囊卵巢（Polycysticovaries）(2outof3criteria)排除其他代謝異常（Exclusionofotheretiologies）

當前24頁，總共31頁。

PCOS的定義(3)高雄激素血癥（Hyperandrogenism）卵巢功能