胰島素抵抗的病理生理機(jī)制和治療選擇課件

胰島素抵抗的病理生理機(jī)制和治療選擇

PathophysiologyandclinictherapystrategyofInsulinResistance

北京協(xié)和醫(yī)院肖新華

MetabolicSyndromeandInflammation:

ANewUnderstandingofIR、HypertensiveCardiovascularDamage1AmericanDiabetesAssociation.DiabetesCare1998;21:310–314;

2Beck-NielsenH&GroopLC.JClinInvest1994;94:1714–1721.3BloomgardenZT.ClinTher1998;20:216–231.

4ReavenP.PhysRev1995;75:66–79.胰島素抵抗的定義

insulinresistance（IR）胰島素抵抗是由遺傳和環(huán)境因素引起，機(jī)體對(duì)胰島素生理作用的反應(yīng)性降低，即胰島素敏感性降低。主要部位在肝臟、肌肉和脂肪組織，使糖耐量受損并最終導(dǎo)致糖尿病。胰島素抵抗常集中了一系列心血管危險(xiǎn)因素—葡萄糖代謝障礙、高血壓、血脂紊亂等，統(tǒng)稱代謝綜合征。代償性高胰島素血癥血脂代謝異常*高血壓葡萄糖耐受不良PAI-1tPA尿酸微血管病變心絞痛胰島素抵抗遺傳向心性肥胖少動(dòng)的生活習(xí)慣冠狀動(dòng)脈疾病胰島素抵抗是代謝綜合征的核心因素動(dòng)脈粥樣硬化是一種慢性炎癥性疾病糖尿病是一種心血管疾病，也是一種炎癥性疾病。

Itisonlyrecentlythatinflammationhasbeenacceptedgenericallyasthecentralmechanism,perhapsthefinalcommonpathwayleadingtotheatheroscleroticprocess.

炎癥性動(dòng)脈粥樣硬化過(guò)程sdLDLsdLDLox-LDL單核細(xì)胞化學(xué)趨化mfO2泡沫細(xì)胞

分化脂紋復(fù)合性(易受損的)斑塊血管腔動(dòng)脈壁內(nèi)皮細(xì)胞炎癥性細(xì)胞因子,IL-6,TNFa

ROS非特異性炎癥指標(biāo),CRPMMP-9-平滑肌細(xì)胞MCP-1斑塊破裂MMPmatrixmetalloproteinases.MCPmonocytechemoattractantprotein

巨噬細(xì)胞

VCAM-1MCP-1COX-2AⅡ血管活性氧生成血管炎癥內(nèi)皮功能障礙（NO利用）致炎癥基因表達(dá)（VCAM-1,MCP-1）LDL氧化心血管事件動(dòng)脈粥樣硬化發(fā)生與發(fā)展LIFEPrimaryCompositeOutcomeDahlofetal,TheLancet,2002;359:995-1003PrimaryCompositeendpointsPrimaryendpoint

13%,p=0.02

Stroke

25%,(p=0.001)CVmortality

11%(p=ns)MI=nsProportionofpatientswithfirstevent(%)06121824303642485460668041216Time(months)AtenololAdjustedRR13.0%,p

=0.021LosartanUnadjustedRR14.6%,p=0.009Otherprespecifiedendpoints

New-onsetDiabetes

25%,p=0.02DecreaseinLVHTotalmortality,p=nsHeartfailure,p=nsVALUE:IncidenceofNew-onsetDiabetesNew-OnsetDiabetes

(%ofpatientsin

treatmentgroup)JuliusS,KjeldsenSE,WeberMetal.Lancet.June2004;363.02468101214Valsartan-basedRegimen(n=5254)Amlodipine-basedRegimen(n=5168)13.1%16.4%23%RiskReductionWithValsartan1618P<0.0001阻斷RAS系統(tǒng)改善胰島素抵抗的機(jī)理ATII增加IR、IRS-1、PI3K的絲氨酸磷酸化，影響胰島素的信號(hào)傳遞，因此降低ATII的作用可改善IR擴(kuò)張血管，改善骨骼肌的血流增加脂聯(lián)素的水平降低肌肉的TNFa水平血管緊張素II與胰島素抵抗ANGII通過(guò)增加胰島素受體B亞單位和IRS-1的絲氨酸磷酸化，降低胰島素誘發(fā)的IRS-1的酪氨酸的磷酸化，使受體與受體底物的親和力下降，導(dǎo)致IR．他汀類藥臨床試驗(yàn)僅能降低心血管終點(diǎn)事件30％左右，冠心病絕不僅是膽固醇過(guò)多的疾病，尚有其他危險(xiǎn)因素.他汀類具有調(diào)脂外作用:對(duì)LDL－C正常者，他汀類藥物仍有心臟保護(hù)作用WOSCOP試驗(yàn)后分析發(fā)現(xiàn)，他汀除有心臟保護(hù)作用外，還使糖尿病的發(fā)病率較對(duì)照降低30％慢性炎癥可能是IR的啟動(dòng)因子

在炎癥與IR的病理生理過(guò)程中

脂源性因子的表達(dá)異常扮演了重要角色.

PickupJC,CrookMADiabetologia1998,41(10):1241AngiotensinogenLeptinAdipocytePlasminogenactivatorinhibitor(PAI-1)Adipsin(ASP)IL-6TNF-aAdiponectinAdiposeTissueasEndocrineCellsResistinTheInsulinSignalingPathwayPPIRSShcGrb2SOSP85P110CrkNckFynCskSHP2RafMEKAkt/PKBPDK1PDK2GLUT1BiosynthesisGLUT4vesiclePI3-KPKBbPKCPKCGlucoseTransportFAKRacPDEFocalAdhesionMembraneRufflingAntilipolysisInsulinReceptorRasERKMAPKGrowthMigrationInsulin

eNOSNOVasodilationIR的主要機(jī)制是氧化應(yīng)激產(chǎn)生的活性氧和活性氮

通過(guò)NF-kB、P38、MAKP及PKC等系統(tǒng)活化，干擾胰島素信號(hào)傳導(dǎo)，引發(fā)GLUT4表達(dá)、轉(zhuǎn)位受抑制。PickupJC,CrookMADiabetologia1998,41(10):1241氧化應(yīng)激

引起胰島素抵抗、糖尿病和心血管疾病的

“共同土壤”CamilloGolgilecture,2004EASD,Munich,GermanyAntonioCeriello主要針對(duì)胰島素抵抗的治療藥物生活方式的改變二甲雙胍PPARs激動(dòng)劑RAS系統(tǒng)抑制劑神經(jīng)肽Y拮抗劑β-3腎上腺素能受體激動(dòng)劑蛋白酪氨酸磷酸酶-1B抑制劑針對(duì)脂肪組織細(xì)胞的治療手段脂聯(lián)素類似物和/或脂聯(lián)素受體激動(dòng)劑抵抗素拮抗劑IL-6/IL-1拮抗劑TNF-α拮抗劑PPARs激動(dòng)劑PeroxisomeProliferatorActivatedReceptor過(guò)氧化物酶增殖子激活受體PPARs的分類PPARα：脂肪組織、肝臟和骨骼肌、腎臟、腸亦可見(jiàn)PPARβ/δ：體內(nèi)普遍存在PPARγPPARγ1：脂肪組織、肝臟、骨骼肌、心臟、腸、腎臟、胰腺、脾可見(jiàn)PPARγ2：脂肪組織PPARγ3：脂肪組織，巨噬細(xì)胞和結(jié)腸上皮JMedChem2000;43:527-550HowdoesPPARgactivationreduceinsulinresistance?PPARgIncreasesGlucoseDisposal:

PotentialSiteofActionCo-repressors(SMRT,N-COR)etc.ActivationofPPARaltersexpressionofspecificgenesencodingkeyproteinscontrollinglipidandglucosemetabolism

RXRPPRE(DR-1)LPL,PEPCK,aP2,PI3K,GLUT-4codingsequencesAGGTCAXAGGTCAPPARTZDretinoicCo-activators(SRC-1,PGC-1)etc.Whatisthesignalfromadiposetissuethatimprovesinsulinactioninliverandskeletalmuscle?Howdothiazolidinedionesregulateadiposetissuemetabolism?HowdoesPPARgactivationreduceinsulinresistance?PPARisthemasterregulatorofpre-adipocytedifferentiation

pre-adipocytesinsulin-responsivesmalladipocytesinsulin-resistantlargeadipocytesPPARgTZDPotentiatesinsulin-stimulateddifferentiationBlockslipolysis&inflammatorycytokinerelease.Pro-apoptoticpre-adipocytesinsulin-responsivesmalladipocytesinsulin-resistantlargeadipocytesThiazolidinedionesshiftfatcellpopulationsinfavourofsmallinsulin-sensitiveadipocytes

InsulinresistantstateThiazolidinedionesshiftfatcellpopulationsinfavourofsmallinsulin-sensitiveadipocytes

pre-adipocytesinsulin-responsivesmalladipocytesinsulin-resistantlargeadipocytes+TZDinsulinsensitivestateRosiglitazonefavourablymodifiesadipocytesecretoryprofilesAdiponectinResistinAngiotensinIITNFaPAI-1FreefattyacidsLeptinPPARgpTyr-IRS1-pTyr-pTyrInsulinreceptorInsulinGrowth&mitogenesisGrb2RasRafMAPKSosShcGlycogensynthesisPTB-1BCAP/cblPKB/AktGlucosetransportGSK-3GS

GS-PPP1-GGLUT-4PKC/PI3KSHIP-2PIP3PIP2TZDTZDTZDTZDTZDTZDSitesofrosiglitazoneactiononinsulinsignallingpathwaysDifferentiationHypertrophyPre-adipocyteSmallAdipocyteLargeAdipocytePPARgOvernutritionInsulinResistance↓InsulinResistance↑TNF-a↑FFA↑TheRoleofPPARginthedifferentiationofAdipocytesKubotaN.etal.:MolecularCell,4,597,1999.Adiponectin↑TZDHyperglycaemiaPancreasLiverMuscleImpairedInsulinsecretion–+MetforminIncreasedglucoseproductionDecreasedglucoseuptakeMetformin:dualsitesofactionp=0.0009p=0.0002HundalRSetal.Diabetes2000;49:2063-9Rate(mmol/m2/min)MetforminreduceshepaticglucoseproductionMetforminandlipidprofilesDeFronzoRA&GoodmanAM.NEJM1995;333:541-9p=0.001p=0.0191ChuNV,etal.DiabetesCare2002;25:542–549.

2KirpichnikovD,etal.AnnIntMed2002;137:25–33.3DeFronzoRA,etal.NewEng.JMed1995;333:541–549.Effectofmetforminoncardiovascularriskfactors-beyondglycemiccontrolDyslipidemiaHypofibrinolysisInflammationReducesPAI-1levels2IncreasesHDL-clevelsDecreasesCRP1Reducesfreefattyacid,triglycerideandLDL-clevels2,3MetforminReducedCVriskfactorsMetformin:multiplemechanismsforreducingcardiovascularriskInsulinsensitivityFibrinolysisNutritivecapillaryflowHaemorrheologyPost-ischaemicflowImprovedReducedHypertriglyceridaemiaAGEformationCrosslinkedfibrinNeovascularisationOxidativestressReducedcardiovascularriskMamputuJCetal.DiabetesMetab2003;29:6S71-6;WiernspergerN&BouskelaE.Diabetes

Metab2003;29:6S77-87;LeverveXMetal.DiabetesMetab2003;29:6S88-94;

Beisswenger&Ruggiero-Lopez.DiabetesMetab2003;29:6S95-103RAS系統(tǒng)抑制劑目前ARB和ACEI已經(jīng)被證實(shí)可改善糖尿病或糖尿病前期患者的胰島素敏感性，因此可能用于糖尿病的治療目前在脂肪組織內(nèi)也有RAS系統(tǒng)發(fā)現(xiàn)，RAS系統(tǒng)可能對(duì)脂肪細(xì)胞的分化、成熟等起作用，同時(shí)通過(guò)調(diào)節(jié)局部血流和脂肪細(xì)胞的體積和數(shù)量發(fā)揮作用；對(duì)脂肪細(xì)胞合成/釋放的細(xì)胞因子可能有直接作用，在脂肪細(xì)胞可能存在不依賴于ACE的ANGⅡ合成途徑

DREAM研究（Ramipril

vs

Rosiglitazone）、NAVIGATOR研究（Valsartan

vs

nateglinide）將證實(shí)干預(yù)RAS系統(tǒng)是否能夠用于糖尿病和心血管事件的預(yù)防和治療藥物預(yù)防糖尿病的可能性β-3腎上腺素能受體激動(dòng)劑β-3腎上腺素能受體是G-蛋白偶聯(lián)的膜受體，主要分布在棕色脂肪組織，主要參與調(diào)節(jié)人體能量平衡β-3腎上腺素能受體的功能與肥胖、胰島素抵抗和2型糖尿病等密切相關(guān)β-3腎上腺素能受體激動(dòng)劑將具有改善胰島素抵抗、降低體重等作用IL6PAI-1TNF脂聯(lián)素Leptin胰島素敏感性胰島素抵抗血管炎癥內(nèi)皮功能異常血管緊張素原FFA脂肪組織脂肪組織因子與胰島素抵抗和炎癥針對(duì)脂肪/組織細(xì)胞的治療手段脂肪組織的內(nèi)分泌功能越來(lái)越重視，針對(duì)脂肪組織/細(xì)胞的治療更多地針對(duì)造成高血糖的病理生理機(jī)制，而非高血糖本身脂聯(lián)素類似物和/或脂聯(lián)素受體激動(dòng)劑抵抗素拮抗劑IL-6/IL-1拮抗劑TNF-α拮抗劑脂聯(lián)素類似物和/或脂聯(lián)素受體激動(dòng)劑肥胖/糖尿病個(gè)體的脂聯(lián)素水平顯著低于正常人群脂聯(lián)素（Adiponectin）具有改善胰島素敏感性、促進(jìn)肌肉對(duì)FFA的攝取，降低循環(huán)中的FFA和TG等水平；抑制動(dòng)脈粥樣硬化病變進(jìn)程等；對(duì)導(dǎo)致2型糖尿病和動(dòng)脈粥樣硬化的炎癥機(jī)制具有