脂肪组织和胰岛素抵抗研究进展课件

单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,脂肪组织和胰岛素抵抗研究进展,The Adipose Tissue and Insulin Resistance,脂肪组织和胰岛素抵抗研究进展,我国糖尿病患病率,9.7%,，其中,2,型糖尿病（,T2DM),占,90%,，绝大多数,T2DM,患者存在,IR,；,IR,定义,：,是指胰岛素效应器官对正常剂量胰岛素反应性降低，,导致胰岛素敏感组织（脂肪、肝脏和肌肉）对,葡萄糖摄取和利用障碍。,胰岛素抵抗（,Insulin resistance,IR),Reaven,1988,Diabetes,胰岛素抵抗（Insulin resistance,IR,胰岛素（,Insulin),的生理功能,Saltiel,AR,Nature,2001,胰岛,细胞分泌的促合成激素,;,促进碳水化合物、脂类和蛋白质合成：刺激葡萄糖、氨基酸和脂肪酸转运入细胞，提高糖原、脂类和蛋白质合成相关酶的表达和活性；,抑制碳水化合物、脂类和蛋白质降解相关酶类的表达，抑制其分解及释放入血。,胰岛素（Insulin)的生理功能Saltiel AR,N,胰岛素抵抗综合征（,IRS),的特征,肥胖（尤腹型肥胖,visceral,obesity,）,糖耐量减低,(Glucose,intorlerance:,impaired,glucose,intolerance;,impaired,fasting,glucose,T2DM),脂代谢紊乱,（,high,triacylglycerol,low,HDL,small dense LDL particles),高血压,内皮功能紊乱,动脉粥样硬化性冠心病,(Atherosclerotic,CVD),高胰岛素血症,胰岛素抵抗,Defronzo RA et al,2010,Diabetologia,胰岛素抵抗综合征（IRS)的特征肥胖（尤腹型肥胖 vi,生理及,IR,时的胰岛素受体后信号通路,IRS,：,胰岛素受体底物,（,Insulin receptor substrate,）,PI3K,:,磷脂酰肌醇,-3-,激酶,GLUT-4,：,葡萄糖转运体,4,(Glucose transporters),Healthy,IR,Defronzo RA et al,2010,Diabetologia,Hypertension,Athersclerosis,生理及IR时的胰岛素受体后信号通路IRS：胰岛素受体底,胰岛素抵抗人群,CVD,发病率显著升高,可能机制：,代偿性高胰岛素血症,抑制肝脏产生和释放过多葡萄糖，但内脏脂肪有过多脂肪分解导致游离脂肪酸释放，并抑制肌肉摄取和利用葡萄糖；,FFA,通过脂毒性促进,AS,的发生,胰岛素抵抗伴随的高血压、高血糖、高血脂等因素导致,内皮功能失调,为起始环节的,AS,的发生。,颈动脉内膜、中膜增厚,是糖尿病患者亚临床,AS,的标志，胰岛素敏感性与颈总动脉内膜、中膜厚度呈负相关。,胰岛素抵抗与动脉粥样硬化性冠心病相关,Defronzo RA et al,2010,Diabetologia,胰岛素抵抗与动脉粥样硬化性冠心病相关Defronzo R,IR,是心血管疾病和,2,型糖尿病发生的共同特征,IR是心血管疾病和2型糖尿病发生的共同特征,肥胖,(Obesity,），,IR,和,T2DM,肥胖,尤其是腹型肥胖，是引起,IR,和,T2DM,最重要的危险因素。,循证医学研究证据：,美国肥胖青少年中,IR,发生率约,50%,；,临床,T2DM,病例约,80%,超重或肥胖；减重、减少内脏脂肪体积等措施可切实改善,IR,即使体脂肪分布“正常”，,脂肪功能失调,（,adipose,tissue dysfunction,）,与,IR,及,T2DM,的发生发展密切相关。,Chan JM,1994,S.Matthaei et al,2000,Goossens GH,2008,肥胖(Obesity），IR 和T2DM 肥胖尤其是腹型,腹部脂肪堆积,（,Visceral Fat Deposition,）,Foster MT,Adipocyte,2012,Visceral,(10%of body total,，,VAT,),is highly associated with,obesity-related health consequences,腹部脂肪堆积（Visceral Fat Deposition,中心型肥胖,（,Central,Obesity,）,与,IR,Foster MT,Adipocyte,2012,中心型肥胖（Central Obesity）与IR Fos,VazquezVela M E,2008,Planat-Benard V,2004,Masoodi M,2014,Pluripotential,fibroblasts,myocytes,chondrocytes and adipocytes,CD34,CD13,positive,TZDs:(,噻唑烷二酮类,),PPAR,agonist,如罗格列酮，匹格列酮,PPAR,:Peroxisome proliferators,-activated receptor,过氧化物酶增殖体激活的受体,PGC-1,：,peroxisome proliferator,-activated,receptor-,coactivator-1,过氧化物酶体增殖物激活受体,辅激活因子,C/EBP,：,CCAAT,增强子结合蛋白,Adipogenesis,lipogenesis,SREBP-1c:adipocyte determination and,differentiation dependent factor 1(ADD1),脂肪细胞定向分化因子,1,PGC-1,脂肪生成（,Adipogenesis,）,VazquezVela M E,2008Plurip,Rosen ED,2006;Masoodi M 2014,脂肪细胞分化的相关信号通路及其细胞内外信号调节,促成脂家族,:,KLFs,STATs1,5A 5B.,抑成脂家族,:,GATA2,3;,SIRT1,Rosen ED,2006;Masoodi M 2014 脂,Preadipocytes,（前脂肪细胞）,Small adipocytes,Large adipocytes,PPAR,:Peroxisome proliferators,-activated receptor,过氧化物酶增殖体激活的受体,PGC-1,：,peroxisome proliferator-activated,receptor-,coactivator-1,过氧化物酶体增殖物激活受体,辅激活因子,TZDs:,噻唑烷二酮类，,PPAR,agonist,如罗格列酮，匹格列酮,C/EBP-,PPAR,脂肪细胞容积调控与,IR,发生密切相关,Rosen ED,2006;Lundgren M,Diabetologia,2007,增生：,Hyperplasia,肥大：,Hypertrophy,Preadipocytes（前脂肪细胞）Small adi,VazquezVela M E,2008,LPL,：脂蛋白脂酶,ATGL:,脂肪三酯酰甘油酯酶,HSL:,激素敏感酯酶,Peripilipin:,围脂滴蛋白,脂肪代谢：生脂作用（,lipogenesis),脂解反应（,lipolysis),乙酰辅酶,A,羧化酶,脂肪酸合成酶,ChREBP,VazquezVela M E,2008LPL：,肥胖、脂肪功能失调和胰岛素抵抗,Enlarged,adipocytes,Obesity:,肥胖,Adipocyte:,脂肪细胞,Adipokines:,脂肪因子,Modified from Goossens GH,2008;Smith U,2002(PMID:12080441),肥胖、脂肪功能失调和胰岛素抵抗EnlargedObesity,Adiponectin:,脂联素,Leptin:,瘦素,TNF-,:,肿瘤坏死因子,IL-6:,白介素,6,Resistin:,抵抗素,脂肪功能失调：脂肪因子分泌紊乱和炎症,Lean state,IR or obesity state,Cao H,2014,Adiponectin:脂联素,Obesity,FFA,inflammation and IR,SchenkS,2008;Skurk T,2007,TLR4 signaling,NF,B signaling,Obesity,FFA,inflammation and,内质网应激是,IR,发生的重要机制,Beck and Kaufman,2012,未折叠反应：,Unfolded protein response,（,UPR,）,内质网跨膜信号蛋白：,PERK,，,ATF6,，,IRE1,内质网应激是IR发生的重要机制Beck and Kaufma,内质网应激与细胞凋亡,Carla J.H.van der Kallen,，,2009,，,Apoptosis,Inflammation,内质网应激与细胞凋亡Carla J.H.van der,Proliferation,differentiation,Adipocyte tissue dysfunction and insulin resistance,Preadipocytes,Small adipocytes,S,Sensitivity to insulin,Obesity/T2DM/IR,proliferation,apoptosis,differentiation,The percentage of small adipocytes,the size of adipocytes,Modified from,Naoto Kubota,Molecular Cell 1999;Ishihara,Y,，,Atherosclerosis,2010;,Lee MH,Kidney Int,2008;Okuno A J Clin Invest,1998,Skurk T,J Clin Endocrinol Metab 2007,Adipocyte tissue,Statins:,e.g.,Pravastatin,Pitovastatin,S,S,Senstivity to insulin,L,L,L,The plasma level of saturated free fatty acids(FFA),IR,Adipocyte tissue dysfunction,Proliferation,differentiation,ClC-3 is important in the regulation of cell volume,proliferation and apoptosis,Evidences:,Duan D,et al.,Nature.,1997;390(6658):417-421.,Yamazaki J,et al.,J Physiol.,1998;507(Pt 3):729-736.,Wang GL,et al.,Circ Res.,2002;91(10):E28-32.,Zhou JG,et al.,J Biol Chem.,2005;280(8):7301-7308.,Zhang HN,et al.,Apoptosis.,2006;11(3):327-336.,Tang YB,et al.,Cell Prolif.,2008;41(5):775-785.,Mao J,et al.,Biochem Pharmacol.,2008;75(9):1706-1716.,Xu B,et al.,Acta Biochim Biophys Sin(Shanghai).,42(6):370-380.,Zhu L,et al.,Biochem Pharmacol.,83(3):324-334.,Guan