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1、脂肪组织和胰岛素抵抗研究进展The Adipose Tissue and Insulin Resistance,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（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
2、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 (Atherosclero
3、tic CVD)高胰岛素血症胰岛素抵抗,Defronzo RA et al, 2010,Diabetologia,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,HypertensionAthersclerosis,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
4、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,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%
5、 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,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 consequenc
6、es,中心型肥胖 （Central Obesity）与IR,Foster MT, Adipocyte,2012,VazquezVela M E,2008Planat-Benard V,2004Masoodi 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
7、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）,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,
8、促成脂家族:KLFs, STATs1,5A 5B. 抑成脂家族:GATA2,3; SIRT1,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,
9、2007,增生：Hyperplasia,肥大：Hypertrophy,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,肥胖、脂肪功能失调和胰岛素抵抗,Enlargedadipocytes,Obesity: 肥胖Adipocyte: 脂肪细胞Adipokines: 脂肪因子,Modified from Goossens GH, 2008; Smith U, 2002(PM
10、ID:12080441),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,Obesity, FFA, inflammation and IR,SchenkS,2008;Skurk T, 2007,TLR4 signalingNFB signaling,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 respons
11、e （UPR）内质网跨膜信号蛋白：PERK，ATF6，IRE1 ,内质网应激与细胞凋亡,Carla J. H. van der Kallen，2009，Apoptosis,Inflammation,Proliferation, differentiation,Adipocyte tissue dysfunction and insulin resistance,Preadipocytes,Small adipocytes,Sensitivity to insulin,Obesity /T2DM /IR,Modified from Naoto Kubota, Molecular Cell 199
12、9; Ishihara, Y，Atherosclerosis,2010; Lee MH, Kidney Int,2008; Okuno A J Clin Invest ,1998, Skurk T, J Clin Endocrinol Metab 2007,Adipocyte tissue,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
13、. 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
14、 Biochim Biophys Sin (Shanghai).42(6):370-380.Zhu L, et al. Biochem Pharmacol.83(3):324-334.Guan YY, et al. Trends Pharmacol Sci. 2006;27(6):290-296.,Sasaki S, et al. ClC family in the kidney, Jpn J Physiol. 1994;44 Suppl 2:S3-8.,ClC-3 is important in the regulation of cellular apoptosis,Liu J, et a
15、l. Apoptosis 2013; Qian Y, et al. Apoptosis 2011,Shi, XL, et al. Hypertension 2007; Liu YJ，et al: Hypertension 2010,ICl,vol and ClC-3 increased in basilar artery during hypertension, simvastatin could normalize the upregulation of ClC-3,Thomas J. Jentsch, et al. The Journal of Neuroscience, October
16、15, 2008. 28(42):1058710598,Serum insulin levels were significantly lower in ClC-3 KO mice,ClC-3 protein is important in the regulation of cellular apoptosis,Zhang HN, Apoptosis,2006; Qian Y, . Apoptosis 2011; Liu J, et al. Apoptosis 2013,ClC-3 encodes volume-regulated chloride channel in vascular s
17、mooth muscle cells and involved in VSMC proliferation,Wang GL, Cir. Res.2002, Zhou JG, JBC,2005,Guan YY, Trends Pharmacol.Sci.,2006,Shi, XL, Hypertension 2007; Liu YJ，Hypertension 2010,ICl,vol and ClC-3 increased in basilar artery during hypertension, simvastatin could normalize the upregulation of
18、ClC-3,Statins,ClC-3,Adipose tissue dysfunction during Insulin Resistance,Improve,Upregulate,Questions: 1, Whether there is a relation between ClC-3 and IR ? 2, If yes, what is the underlying mechanism?,Preadipocytes of T2DM subjects display an intrinsic gene expression profile of enhanced apoptosis.
19、,van Tienen FH, et al. Int J Obes (Lond).2011.35(9):1154-1164.,The high-sucrose-fat diet (HSFD) and streptozotocin (STZ) -induced diabetic rats exhibits enhanced ClC-3 protein expression in adipose tissue, which is positively correlated with HOMA-IR values,Huang YY, 2014,2型糖尿病大鼠肝脏及骨骼肌组织ClC-3蛋白质表达与IR
20、无明显相关性,HOMA-IR values had no relevance to ClC-3 protein expression of liver or skeletal muscle in HSFD/STZ-induced diabetic rats,Huang YY, 2014,脂肪ClC-3蛋白表达与TG、FFA、磷酸化HSL水平呈正相关,与adiponectin水平呈负相关,The HSFD/STZ-induced diabetic rats exhibited elevated serum TG and FFAs levels, both were positively corr
21、elated with ClC-3 protein expression in adiposetissue,Huang YY, 2014,ClC-3 KO mice challenged with HSFD/STZ exhibited reduced HOMA-IRvalues, AUC of ITTs and serum FFAs levels,Huang YY, 2014,ClC-3 silencing could improve glucose and lipid disorders, as well as impaired insulin sensitivity in T2DM,Dat
22、a are presented as means S.E., n=12.*P 0.05 vs WT group. *P 0.01 vs WT group. #P 0.05 vs WT-T2DM group. #P 0.01 vs WT-T2DM group.,Data are presented as means S.E., n=12.*P 0.05 vs WT group. *P 0.01 vs WT group. #P 0.05 vs WT-T2DM group. #P 0.01 vs WT-T2DM group.,Effect of ClC-3 knockout on metabolic
23、 parameters of HSFD/STZ-treated diabetic mice,Huang YY, 2014,Jentsch, TJ. J. Neurosci., 2008,Serum insulin levels were significantly lower, but neither hyperglycemia nor rebound hypoglycemia in ClC-3 KO mice,Neither hyperglycemia nor rebound hypoglycemia was shown following a glucose load in ClC-3-/
24、- mice,Dickerson LW, Brain Res,2002.,ClC-3 KO mice challenged with HSFD/STZ exhibited reduced preadipocyte apoptosis,Huang YY, 2014,Palmitate increased ClC-3 mRNA expression in 3T3-L1 preadipocytes using real-time RT-PCR analysis,Huang YY, 2014,Palmitate increased ClC-3 protein expression in 3T3-L1
25、preadipocytes,Huang YY, 2014,Palmitate increased apoptosis and ClC-3 expression in 3T3-L1 preadipocytes, and both increases have a positive correlation,Huang YY, 2014,ClC-3 siRNA significantly improved palmitate-induced apoptosis in 3T3-L1 preadipocytes,Huang YY, 2014,The activation of caspases indu
26、ced by palmitate in preadipocytes could be significantly reduced by ClC-3 siRNA,Huang YY, 2014,Palmitate reduced the antiapoptic Bcl-2 expression and Bcl-2/Bax ratio, which could be significantly normalized by ClC-3 siRNA,Huang YY, 2014,ER stress induce apoptosis in diabetes,ClC-3 siRNA alleviatedpa
27、lmitate-induced GRP78 protein expression in preadipocytes,Huang YY, 2014,ClC-3 siRNA alleviatedpalmitate-induced CHOP and ATF4 protein expression in preadipocytes,Huang YY, 2014,ClC-3 siRNA didnt affectpalmitate-induced p-eiF2 or p-PERK protein expression in preadipocytes,ClC-3 siRNA alleviatedpalmi
28、tate-induced p-JNK1/2 protein expression in preadipocytes,Huang YY, 2014,ClC-3 siRNA,Summary,1.ClC-3 deficiency could improve the enhanced preadipocyte apoptosis, hyperglycemia and hyperlipidmia, and insulin resistance during T2DM2. ClC-3 protein is required for ER-stress dependent preadipocyte apoptosis induced by palmitate, but not oleate. 3.These data suggest that ClC-3 may serve as a novel potential target to prevent metabolic disruption in the development of insulin resistance and T2DM,
