胰島素抵抗的病理生理機(jī)制和治療選擇

1、胰島素抵抗的病理生理機(jī)制和治療選擇胰島素抵抗的病理生理機(jī)制和治療選擇Pathophysiology and clinic therapy strategy of Insulin Resistance北京協(xié)和醫(yī)院肖新華北京協(xié)和醫(yī)院肖新華 Metabolic Syndrome and Inflammation: A New Understanding of IR、Hypertensive Cardiovascular Damage1American Diabetes Association. Diabetes Care 1998; 21:310314; 2Beck-Nielsen H &

2、Groop LC. J Clin Invest 1994; 94:17141721. 3Bloomgarden ZT. Clin Ther 1998; 20:216231. 4Reaven P. Phys Rev 1995; 75:6679.胰島素抵抗的定義 insulin resistance（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。代償性代償性高胰島素血癥高胰島素血癥血脂代謝血脂代謝

3、異常異常* *高血壓高血壓葡萄糖葡萄糖耐受不良耐受不良 PAI-1PAI-1 tPAtPA 尿酸尿酸微血管病變微血管病變心絞痛心絞痛胰島素抵抗胰島素抵抗遺傳遺傳向心性肥胖向心性肥胖少動(dòng)的生活習(xí)慣少動(dòng)的生活習(xí)慣 冠狀動(dòng)脈疾病冠狀動(dòng)脈疾病胰島素抵抗是代謝綜合征的核心因素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，也是一種炎癥糖尿病是一種心血管疾病，也是一種炎癥性疾病。性疾病。 It is only recently that inflammation has been accepted generically as the

4、 central mechanism, perhaps the final common pathway leading to the atherosclerotic process. Atherosclerosis: An Inflammatory Disease炎癥性動(dòng)脈粥樣硬化過程sdLDLsdLDLox-LDL單核細(xì)胞單核細(xì)胞化學(xué)趨化化學(xué)趨化mf fO2泡沫細(xì)胞泡沫細(xì)胞 分化 脂紋脂紋復(fù)合性復(fù)合性(易受損的易受損的)斑塊斑塊血管腔血管腔動(dòng)脈壁動(dòng)脈壁內(nèi)皮細(xì)胞內(nèi)皮細(xì)胞炎癥性細(xì)胞因子炎癥性細(xì)胞因子,IL-6, TNFa a ROS非特異性炎癥指標(biāo)非特異性炎癥指標(biāo),CRPMMP-9-平滑肌細(xì)胞

5、平滑肌細(xì)胞MCP-1斑塊破裂斑塊破裂MMP matrix metalloproteinases . MCP monocyte chemoattractant protein 巨噬細(xì)胞巨噬細(xì)胞 MCP-1 Monocyte chemoattractant protein-1 ICAM-1 Intercellular adhesion molecule-1 VCAM-1 Vascular cell adhesion molecule MMPs Matrix metalloproteinases VCAM-1 MCP-1COX-2A 血管活性氧生成血管活性氧生成 血血 管管 炎炎 癥癥內(nèi)皮功能障礙內(nèi)

6、皮功能障礙（NO利用）利用） 致炎癥基因表達(dá)致炎癥基因表達(dá)（VCAM-1,MCP-1）LDL氧化氧化心血管事件心血管事件動(dòng)脈粥樣硬化發(fā)生與發(fā)展動(dòng)脈粥樣硬化發(fā)生與發(fā)展RAS and insulin resistance RAS must also be considered in the development of insulin resistance. Treatment with ACEI and ARB may improve insulin sensitivity and prevent the development of type2 diabetes.Dahlof et al, T

7、he Lancet,2002; 359:995-1003Primary Composite endpointsProportion of patients with first event (%)061218243036 42 4854 60668041216Time (months)AtenololAdjusted RR 13.0%, p = 0.021LosartanUnadjusted RR 14.6%, p = 0.009Other prespecified endpointsVALUE: Incidence of New-onset DiabetesNew-Onset Diabete

8、s (% of patients in treatment group)Julius S, Kjeldsen SE, Weber M et al. Lancet. June 2004;363.02468101214Valsartan-based Regimen(n = 5254)Amlodipine-based Regimen(n = 5168)13.1%16.4%23% Risk Reduction With Valsartan1618P 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

9、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通過增加胰島素受體B亞單位和亞單位和IRS-1的絲氨酸磷酸化，降低胰島素誘發(fā)的的絲氨酸磷酸化，降低胰島素誘發(fā)的IRS-1的的酪氨酸的磷酸化，使受體與受體底物的親和酪氨酸的磷酸化，使受體與受體底物的親和力下降，導(dǎo)致力下降，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)LDLC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

10、慢性炎癥可能是IR的啟動(dòng)因子在炎癥與IR的病理生理過程中脂源性因子的表達(dá)異常扮演了重要角色.Pickup JC,Crook MA Diabetologia 1998,41(10):1241AngiotensinogenLeptinAdipocyte Plasminogen activator inhibitor (PAI-1)Adipsin (ASP) IL-6TNF-aAdiponectinAdipose Tissue as Endocrine CellsResistinThe Insulin Signaling PathwayPPIRSShcGrb2SOSP85P110CrkNckFynC

11、skSHP2RafMEKAkt/PKBPDK1PDK2GLUT1BiosynthesisGLUT4 vesiclePI3-KPKBbPKC PKC Glucose TransportFAKRacPDEFocal AdhesionMembrane RufflingAntilipolysisInsulin ReceptorRasERK MAPKGrowthMigrationInsulineNOSNO VasodilationIR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。Pickup JC,Croo

12、k MA Diabetologia 1998,41(10):1241氧化應(yīng)激氧化應(yīng)激 引起胰島素抵抗、糖尿病和心血管疾病的引起胰島素抵抗、糖尿病和心血管疾病的“共同土壤共同土壤”Camillo Golgi lecture,2004 EASD, Munich,GermanyAntonio Ceriello主要針對(duì)胰島素抵抗的治療藥物生活方式的改變生活方式的改變 二甲雙胍 PPARs 激動(dòng)劑 RAS系統(tǒng)抑制劑 神經(jīng)肽 Y 拮抗劑 -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

13、-1拮抗劑TNF-拮抗劑PPARs 激動(dòng)劑Peroxisome Proliferator Activated Receptor過氧化物酶增殖子激活受體PPARs的分類 PPAR：脂肪組織、肝臟和骨骼肌、腎臟、腸亦可見 PPAR/：體內(nèi)普遍存在 PPAR PPAR1：脂肪組織、肝臟、骨骼肌、心臟、腸、 腎臟、胰腺、脾可見 PPAR2：脂肪組織 PPAR3：脂肪組織，巨噬細(xì)胞和結(jié)腸上皮J Med Chem 2000;43:527-550How does PPARg activation reduce insulin resistance? PPARg Increases Glucose Dispo

14、sal:Potential Site of ActionCo-repressors(SMRT, N-COR)etc.Activation of PPARg alters expression of specific genes encoding key proteins controlling lipid and glucose metabolism RXRPPRE (DR-1)LPL, PEPCK, aP2,PI3K, GLUT-4coding sequencesAGGTCA X AGGTCAPPARg gTZDretinoicCo-activators(SRC-1, PGC-1)etc.W

15、hat is the signal from adipose tissue that improves insulin action in liver and skeletal muscle ?How do thiazolidinediones regulate adipose tissue metabolism?How does PPARg gactivation reduce insulin resistance? PPARg g is the master regulator of pre-adipocyte differentiation pre-adipocytesinsulin-r

16、esponsivesmall adipocytesinsulin-resistantlarge adipocytesPPARgTZDPotentiates insulin-stimulateddifferentiationBlocks lipolysis & inflammatory cytokine release. Pro-apoptoticpre-adipocytesinsulin-responsivesmall adipocytesinsulin-resistantlarge adipocytes Thiazolidinediones shift fat cell popula

17、tions in favour of small insulin-sensitive adipocytes Insulin resistant state Thiazolidinediones shift fat cell populations in favour of small insulin-sensitive adipocytes pre-adipocytesinsulin-responsivesmall adipocytesinsulin-resistantlarge adipocytes+ TZD insulin sensitive stateRosiglitazone favo

18、urably modifies adipocyte secretory profiles Adiponectin Resistin Angiotensin II TNF aa PAI-1 Free fatty acids Leptin PPARg gpTyr-IRS1-pTyr-pTyrInsulinreceptorInsulinGrowth & mitogenesisGrb2RasRafMAPKSosShcGlycogensynthesisPTB-1BCAP/cblPKB/AktGlucosetransportGSK-3GS GS-PPP1-GGLUT-4PKC / / PI3KSH

19、IP-2PIP3PIP2TZD TZD TZD TZD TZD TZD Sites of rosiglitazone action on insulin signalling pathwaysDifferentiationHypertrophyPre-adipocyteSmall AdipocyteLarge AdipocytePPARg gOver nutritionInsulin ResistanceInsulin ResistanceTNF-a aFFAThe Role of PPARg in the differentiation of AdipocytesKubota N.et al

20、.:Molecular Cell,4,597,1999.AdiponectinTZDHyperglycaemiaPancreasLiverMuscleImpairedInsulin secretion + +MetforminIncreasedglucoseproductionDecreasedglucoseuptakeMetformin: dual sites of actionp=0.0009p=0.0002Hundal RS et al. Diabetes 2000;49:2063-9Rate (mmol/m2/min)Metformin reduces hepatic glucose

21、productionMetformin and lipid profilesDeFronzo RA & Goodman AM. NEJM 1995;333:541-9p=0.001p=0.0191Chu NV, et al. Diabetes Care 2002; 25:542549. 2Kirpichnikov D, et al. Ann Int Med 2002; 137:2533. 3DeFronzo RA, et al. New Eng.J Med 1995; 333:541549.Effect of metformin on cardiovascular risk facto

22、rs - beyond glycemic controlDyslipidemiaHypofibrinolysisInflammationReduces PAI-1 levels2Increases HDL-c levelsDecreases CRP1Reduces free fatty acid, triglyceride and LDL-c levels2,3MetforminReduced CV risk factorsMetformin: multiple mechanisms for reducing cardiovascular risk Insulin sensitivity Fi

23、brinolysis Nutritive capillary flow Haemorrheology Post-ischaemic flowImprovedReduced Hypertriglyceridaemia AGE formation Crosslinked fibrin Neovascularisation Oxidative stressReduced cardiovascular riskMamputu JC et al. Diabetes Metab 2003;29:6S71-6; Wiernsperger N & Bouskela E. Diabetes Metab

24、2003;29:6S77-87; Leverve XM et al. Diabetes Metab 2003;29:6S88-94;Beisswenger & Ruggiero-Lopez. Diabetes Metab 2003;29:6S95-103RAS系統(tǒng)抑制劑 目前目前ARB和和ACEI已經(jīng)被證實(shí)可改善糖尿病或糖尿已經(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病前期患者的胰島素敏感性，因此可能用于糖尿病的治療的治療 目前在脂肪組織內(nèi)也有目前在脂肪組織內(nèi)也有RASRAS系統(tǒng)發(fā)現(xiàn)，系統(tǒng)發(fā)現(xiàn)，RASRAS系統(tǒng)可能系統(tǒng)可能對(duì)脂肪細(xì)胞的分化、成熟等起作用，同時(shí)

25、通過調(diào)節(jié)對(duì)脂肪細(xì)胞的分化、成熟等起作用，同時(shí)通過調(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)胞合成肪細(xì)胞合成/ /釋放的細(xì)胞因子可能有直接作用，在釋放的細(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脂肪細(xì)胞可能存在不依賴于ACEACE的的ANG ANG 合成途徑合成途徑 DREAM DREAM研究（研究（Ramipril vs RosiglitazoneRamipril vs Rosiglitazone）、）、 NAVIGATORNAVIGATOR研究（研究（Valsartan vs nateglinideValsartan vs nat

26、eglinide）將）將證實(shí)干預(yù)證實(shí)干預(yù)RASRAS系統(tǒng)是否能夠用于糖尿病和心血管事件系統(tǒng)是否能夠用于糖尿病和心血管事件的預(yù)防和治療的預(yù)防和治療藥物預(yù)防糖尿病的可能性藥物預(yù)防糖尿病的可能性-3 腎上腺素能受體激動(dòng)劑 -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 -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) -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-1TNFa a脂聯(lián)素脂聯(lián)素Leptin胰島素敏感性胰島素敏感性胰島素抵抗胰島素抵抗血管炎癥血管炎癥內(nèi)皮功能異常內(nèi)皮功能異常血管緊張素原血管緊張素原

27、FFA脂肪組織因子與胰島素抵抗和炎癥針對(duì)脂肪針對(duì)脂肪/組織細(xì)胞的治療手段組織細(xì)胞的治療手段 脂肪組織的內(nèi)分泌功能越來越重視，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-拮抗劑脂聯(lián)素類似物和/或脂聯(lián)素受體激動(dòng)劑 肥胖肥胖/ /糖尿病個(gè)體的脂聯(lián)素水平顯著低于正常人群糖尿病個(gè)體的脂聯(lián)素水平顯著低于正常人群 脂聯(lián)素（脂聯(lián)素（AdiponectinAdiponectin）具有改善胰島素敏感性、促）具有改善胰島素敏感性、促進(jìn)肌肉對(duì)進(jìn)肌肉對(duì)FFAFFA的攝取，降低循環(huán)中的的攝取，降低循環(huán)中的FFA和TG等水平；等水平；抑制動(dòng)脈粥樣硬化病變進(jìn)程等；對(duì)導(dǎo)致抑制動(dòng)脈粥樣硬化病變進(jìn)程等；對(duì)導(dǎo)致2 2型糖尿病和型糖尿病和動(dòng)脈粥樣硬化的炎癥機(jī)制具