脂联素与代谢综合征

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【摘要】 脂联素(APN)在+276T/G、+45T/G、164I/T、+10211T/G、 -11391G/A、-11377G/C等位点的基因多态性与代谢综合征(MS)及其相关性疾病有关。APN水平与三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)独立相关,血清APN水平降低是独立于体脂因素的胰岛素敏感性的因素之一,APN与2型糖尿病(T2DM)呈强负相关,APN水平与高血压发病呈独立负相关,低APN水平是MS的一个独立危险因素,血清APN水平降低是MS的特征性标志。APN水平与无粥样斑块的颈动脉内膜中层厚度呈负相关,是动脉粥样硬化早期的独立预测因子。APN与MS密切相关。

【关键词】 代谢综合征;脂联素;动脉硬化症

Adiponectin and metabolic syndrome

JIANG Hai-bin, SHI Ya-xiong, et al. Department of Endocrinology, The Second Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China

【Abstract】 Adiponectin gene polymorphisms +276T/G、+45T/G、164I/T、+10211T/G、 -11391G/A、-11377G/C are associated with metabolic syndrome,relating with other diseases, including obesity, dyslipidaemia, hypertension, Type 2 diabetes mellitus, atherosclerotic, cardiovascular diseases. The level of adiponectin is independently associated with triglyceride(TG), total cholesterol (TC),low-density lipoprotein(LDL) cholesterol and high-density lipoprotein(HDL) cholesterol. Low plasma concentration of adiponectin (hypoadiponectinaemia )is one of the factors leading to insulin resistance which is independent of body fat. Adiponectin is strongly and inversely associated with type 2 diabetes. Hypoadiponectinaemia were found to be independently associated with a higher risk for the development of hypertension. Circulating adiponectin level is a strong risk marker for metabolic syndrome and hypoadiponectinaemia is a special sign of metabolic syndrome. Circulating adiponect level, which is inversely associated with carotid (without plaque) intima-media thickness(C-IMT),independently predicts atherosclerosis in early stage. Adiponectin is associated closely with metabolic syndrome.

【Key words】 Adiponectin; Metabolic syndrome; Atherosclerosis

代谢综合征(metabolic syndrome,MS)主要表述的是心血管病的多种代谢危险因素在个体内积聚的状态:体脂分布异常、组织胰岛素抵抗、持续低度炎症反应、脂肪细胞因子分泌调控异常。脂联素(adiponectin,APN)具有减轻体质量、改善胰岛素抵抗、炎症负性调控、改善糖脂代谢、拮抗动脉粥样硬化等作用。近年研究发现,APN及其基因型与MS密切相关,本文作以下综述。

1 脂联素概述

APN一般仅由脂肪细胞分泌,是一种特异性蛋白质,血清中的正常浓度为5～30 mg/L。其分子质量为28 ku,由244个氨基酸组成(鼠类同源物为247个氨基酸),APN蛋白(full-length adiponectin protein,fAd)包含一个氨基端的信号肽,一个小的非同源序列,一段由22个胶原重复序列构成的胶原区和一个羧基端的球状结构域(globular cterminal domain,gAd)。在血液中以多种多聚体的形式存在,通过其胶原结构域形成低分子量(LMW)、中分子量(MMW)及高分子量(HMW)三种主要聚合物形态。它是可溶性防御性胶原家族的一个成员.与胶原Ⅷ、x、补体Clq及TNF-α有高度的同源性,TNF-α是APN启动子活性的强抑制剂。APN受体(adipoR)完全跨膜蛋白,包含7个穿膜域,N端在内,C端在外。AdipoR1在全身广泛表达,并丰富表达于骨骼肌,而AdipoR2丰富表达于肝脏。不同物种或同一物种不同类别甚至不同组织如肌肉、肝脏、脂肪、β细胞、心脏血管等,AdipoR1和AdipoR2表达都可不一样。APN结合AdipoR1的C端细胞外结构域,N端胞浆区结构域则与APPL(含有PH结构域、磷酸酪氨酸结合域和亮氨酸拉链结构的衔接蛋白)结合[1]。APN与受体结合后激活APPL,经AMPK、PPARα、促分裂原活化蛋白激酶(MAPK)以及环磷酸腺苷-蛋白激酶A(cAMP-PKA)等途径信号转导,产生下游生物效应:影响胰岛素分泌、调节脂类氧化葡萄糖摄取、抑制巨噬细胞转化、抑制血管平滑肌细胞增殖等。

2 脂联素基因多态性与代谢紊乱及心血管疾病

人类APN基因长17 kb,位于染色体3q27,全基因组扫描显示该位点是T2DM和MS的易感位点,包括分子量从18～4277 bp的三种外显子和大小为0.8 bp和12 bp的两个内含子。APN基因外显子、启动子、甚至内含子单核苷酸基因多态性影响着APN水平及代谢表型,在不同地区、种族亦有差异。目前发现MS等有关APN基因多态性位点有:+276T/G、+45T/G、164I/T、+10211T/G、 -11391G/A、-11377G/C等。

在日本人中发现,276位点G/G基因型的患者患2型糖尿病(T2DM)的几率大大增加,276位点为G/G基因型的患者胰岛素抵抗指数增高,276位G等位点与低血降APN及高体质量指数水平呈线性相关[2]。有报道[3]在T2DM患者中+276T/G多态性位点和冠心病有关,TT纯合子发生冠心病的危险低于其他基因型的携带者。有报道[4]+276T/G多态性位点G>T,在肥胖患者APN水平更高,神经性厌食患者胆固醇水平更高,正常体质量女性中HbA1C水平更低,而这种多态性位点可以导致肥胖或者神经性厌食患者的出现不同代谢表型。

日本人中携带45位点G/G基因型的患者患T2DM的几率大大增加[2],其等位基因G是日本人MS和动脉硬化症发展的危险因子[5]。Kim[6]等对研究结果显示,APN基因多态性+45T>G与T2DM的颈动脉硬化斑块有关,可能导致T2DM的动脉粥样硬化。Fumeron[7]等研究显示+45T/G的携带者中,GG携带者发展成为高血糖症的危险性最大,3年后携带GG基因型的个体体重指数(BMI)及腰臀比的增长较其他基因型个体更为明显。Menzaghi[8]等的研究表明,由以上两个多态性位点组成的单倍型与高加索人的胰岛素抵抗综合征有关。Berthier[9]等对加拿大男性的研究结果却显示,T45G基因G等位基因携带者较T/T基因型有较高的APN浓度。杜鹏飞等[10]进行的45T/G多态性与胰岛素抵抗的相关性研究结果显示T/T者的体质量指数和胰岛素水平较高、胰岛素抵抗程度较重、高密度脂蛋白水平较低,但此研究者未发现45T/G多态性与APN水平的相关性。Salmenniemi[11]等研究发现APN基因外显子45T/G这种同义突变与MS没有明显相关性。

Fumeron[7]等研究发现血糖正常的的个体3年中发生高血糖症的危险与-11391G/A多态性位点有关,对于-11391G/A 的携带者来说,这种危险在GA携带者中增加。Ohashi[12]n等研究发现在日本人中I164T突变携带者的血浆APN水平与无该突变者相比较低,并独立于BMI存在。I164T携带者有一系列MS的临床表现。Vimaleswara[13]等研究发现在亚洲印度人中第一个内含子多态性位点+10211TG 与T2DM、肥胖、低APN血症有关。

Patel[14]等报道-11377 G等位基因频率与颈动脉内膜中层厚度增加有关。Walker[15]等在健康人群中研究发现,APN基因启动子区SNP C-11377G的变异与颈动脉内膜中层厚度相关,且独立于APN水平。Hoefle[16]等研究发现在冠状动脉造影的男性中-11377C>G启动子基因多态性与血清APN降低有关,与冠状动脉狭窄有关,是血管事件的前兆。Vasseur[17]等的研究显示-11377 G/G单倍体与血浆低APN水平和T2DM有关。Sun[18]等研究发现存在-11377/45 CGTT T2DM人对罗格列酮的疗效更好。

3 脂联素与代谢综合征

临床研究[19]证实低APN血症与MS密切相关,相关性疾病包括肥胖、血脂代谢紊乱、高血压、T2DM、动脉粥样硬化性心血管疾病等。Xydakist[20]研究指出,MS相关组分出现的数量与血清中APN水平逐渐降低呈平行改变,APN作为MS独立的预测因子,APN每增加1 mg/L,MS风险比下降17%。低APN水平是MS的一个独立危险因素,独立于肥胖、胰岛素抵抗及炎症标志物[21],血清APN水平降低是MS的特征性标志,血清APN水平下降的可能机制有:①肿瘤坏死因子-α负反馈机制;②内脏肥胖脂肪细胞缺陷;③肥胖脂肪细胞分泌APN相对减少。

3.1 脂联素与肥胖 前瞻性研究[22]中发现恒河猴发生肥胖的早期阶段APN水平就有下降。Milan[23]等在动物实验结果发现 ,给啮齿类动物予APN可以预防由饮食导致的体质量增加,说明低APN血症在肥胖的发生中起重要作用。Lele[24]等研究发现,健康志愿者血清中富含APN,而肥胖者血清APN水平明显低于非肥胖者。肥胖个体的APN浓度明显低于非肥胖者,而当体质量减轻后,APN浓度又升高[25],尽管合成激素的组织量减少,其浓度依然增加,这表明APN在肥胖症患者中的表达可能存在负反馈抑制,肥胖患者APNmRNA表达下降及旁分泌肿瘤坏死因子-α增多,抑制APN分泌。腹内型肥胖者的APN水平降低的程度更为明显,这提示内脏脂肪与APN之间存在更紧密的联系[26],可能与腹内型肥胖者高分子质量的APN水平是下降有关。APN是一个反映长时间体质量变化的指标,低APN血症长时间伴随肥胖,相互交叉影响。

3.2 脂联素与胰岛素抵抗(IR)Yamauchi[27]等及Berg[28]分别报道重组APN能同时改善肥胖和脂肪营养不良小鼠的胰岛素敏感性,降低1 型及2 型糖尿病模型小鼠的血糖。APN通过四个机制增加胰岛素敏感性:①增加脂肪氧化;②直接促进胰岛素受体及受体后信号传导;③抑制葡萄糖异生;④抑制脂肪组织TNF-α信号。高脂喂养的APN基因敲除[29]小鼠呈现严重的IR,杂合子APN缺陷大鼠表现为轻度的胰岛素抵抗而纯合子APN缺陷大鼠表现为明显的胰岛素抵抗。adipo(-/-)小鼠显示通过削弱胰岛素在肝脏的信号而引起肝脏胰岛素抵抗,而肌肉及肝脏的三酰甘油水平没有升高可能和上调瘦素敏感性有关[30]。Semple[31]等研究显示APN水平可以用来鉴别胰岛素受体功能失调有关的严重胰岛素抵抗,当APN>7 mg/L时,有97%预测价值;

3.3 脂联素与脂代谢紊乱 Maeda[33]等研究表明APN与三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)独立相关。Matsubara[34]、Dietrich[35]、Marso[36]等证明,血清APN浓度不仅与TG水平、总胆固醇及载脂蛋自B和E呈负相关,而且与血清HDL-C和载脂蛋白A-l呈正相关。Mitsutake[37]等的研究表明在代谢因素中HDL-C的降低对于预测冠状动脉粥样硬化较APN有用。前瞻性研究[38]表明,在患者已发生急性冠脉事件后,脂代谢紊乱与预后有关,而APN与预后无关。他汀类药物治疗研究[39]中,存在脂代谢紊乱的T2DM患者可以通过降低LDL-C 和TG达到抗动脉粥样硬化,还可以通过升高APN达到目的,其过程与细胞粘附因子有关,有报道[40]普伐他汀可以增加血清APN水平,可能是降脂同时的协同效应,其原因尚未明确。但也有报道[41]阿托伐他汀治疗存在脂代谢紊乱的T2DM患者,不影响APN水平。

3.4 脂联素与糖尿病 前瞻性研究[42]糖尿病发病过程的实验发现。恒河猴肥胖早期APN水平就已下降,至发展为T2DM。其水平继续下降,且APN浓度与胰岛素抵抗、糖尿病发展呈平行关系。临床研究也发现[43]测定健康人、T2DM及T2DM伴肥胖症患者血浆APN水平,发现T2DM组和T2DM伴肥胖症组的空腹APN水平低于正常组,T2DM伴肥胖症组则更低。Heidemann[44]等报道APN与T2DM呈强负相关。韩国的研究[45]显示APN水平与T2DM流行增加负相关。芬兰的前瞻研究[46]显示,APN水平处于低四分位组有更多的人发展位糖调节异常和T2DM。血清APN水平降低可以作为未来发生T2DM、MS的指标[47],血清APN水平升高则发生T2DM的风险降低[48]。

3.5 脂联素与高血压多数研究证实,APN水平与高血压呈负相关。Li[49]等报道APN水平与高血压呈负相关。Ebinc[50]等报道,在高血压合并糖尿病患者中,APN水平较正常血压糖尿病患者明显下降,多元回归分析,其独立于年龄、性别、BMI 和 HOMA-IR。Adamezak[51]等的研究及Shankar[52]等的研究中发现,APN在高血压者较正常血压者明显下降,舒张压、平均动脉血压均呈明显负相关。APN水平与高血压发病呈独立负相关,认为低APN血症是高血压的独立预测因子,与Imatoh[53]等的前瞻性研究结果一致。Koji[54]等的研究则提示APN治疗可以降低肥胖导致的高血压,这为APN用于MS的治疗提供了证据。

4 脂联素与动脉粥样硬化

脂联素有潜在的抗动脉粥样硬化的作用,通过①抑制血管内皮细胞炎性反应及黏附;②抑制巨噬细胞向泡沫细胞转化;③抑制血管平滑肌细胞增殖;④改善糖、脂代谢紊乱等与促炎和抗炎分子,补体分子,生长因子和信号传导蛋白,它们一起调节炎症、代谢和心血管事件[55,56]。

低APN血症与MS和动脉粥样硬化都存在相关[57]。Bernhard[58]等发现APN水平与无粥样斑块的颈动脉内膜中层厚度呈负相关,是动脉粥样硬化早期的独立预测因子。随着MS相关组分出现的数量的增加,APN水平进行性下降,动脉硬化的严重程度进行性增加。Bang[59]等发现有症状的颅内动脉硬化与APN水平下降有关。Stamatis[60]等的研究表明低的血清APN浓度是首次心脏缺血事件后5年死亡率增加的独立预测因子。Lim[61]等在韩国人的研究发现,低的血清APN浓度是T2DM心血管事件发展的危险因子。 Frystyk[62]通过10年随访证明,升高血清APN水平与冠心病低危险相关联,并指出血清APN是老年冠心病的预测指标。

Laughlin[63]通过20年随访,尽管低危人群高APN浓度减少男性冠心病流行40%,但血管造影冠心病患者高APN却增加心血管病和全因死亡近40%。Cavusoglu[64]观察心绞痛和ACS患者,随访两年,指出高APN水平增加全因死亡,并指出APN是强的独立预后预测因子。Teoh[65]解释为:急性心血管损伤(高度炎症状态)显示APN上调反应,高危患者尽管动员所有对抗机制,而机体在修复过程中可以势不可挡转向高心血管死亡率。但高危患者本身可能存在APN抵抗,其机制可能涉及:①受体前:由于患者胰岛素抵抗不断加重,具有显著保护效应的高分子量(HMW)APN减少,占总APN比例下降[66],虽然APN水平正常或升高,但生物活性下降;②受体部位:胰岛素抵抗和高糖环境使APN受体(AdipoR1和/或AdipoR2)表达减少[67,68]。③受体后:具有磷酸化作用的AMPK在高糖环境中活性下降,APN受体后下游信号转导障碍 [69]。

5 展望

在于鉴别MS是否存在相关并发症和心血管风险时,APN水平将会是一个有用的指标,同时,APN水平可以用于评价哪些胰岛素抵抗患者可以从胰岛素增敏剂的治疗中获益,APN本身也可以用于治疗这一部分患者。而MS患者中,APN基因多态性的检测与C-IMT关系的研究,有利于阐述其发病机制和病理生理,有利于研究药物的靶向治疗,有利于筛选合适的治疗人群。

参 考 文 献

[1] Mao X, Kikani C, Riojas R, et al. APPL1 binds to adiponectin receptors and mediates adiponectin signaling and function. Nat. Cell Biol.2006,8:516-523.

[2] Hare K,Boutin P,Mori Y.Genetic variation in the gene encoding adiponectin is associated risk of type 2 diabetes in the Japanese population.Diabetes,2002;51(4):1294.

[3] Qi I .LiT,Rimm E,et al. The+276 polymorphism of the APml gene.plasma adiponectin concentration,and cardiovascular risk in diabetic men.Diabetes,2005,54(5):1607-1610.

[4] Krizova J, Dolinkova M, Lacinova Z,et al.Adiponectin and resistin gene polymorphisms in patients with anorexia nervosa and obesity and its influence on metabolic phenotype.Physiol Res,2008,57(4):539-546

[5] Katsuda Y, Asano A, Murase Y,et al.Association of genetic variation of the adiponectin gene with body fat distribution and carotid atherosclerosis in Japanese obese subjects.J Atheroscler Thromb,2007,14(1):19-26.

[6] Kim SH, Kang ES, Hur KY,et al.Adiponectin gene polymorphism 45T>G is associated with carotid artery plaques in patients with type 2 diabetes mellitus.Metabolism,2008,57(2):274-279.

[7] Fumeron F,Auhert R•Siddiq A,et al.Adiponectin Gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3 year period.The epidemiologic data on the insulin resistance syndrome prospective study.Diabetes,2004,53(4):1150-1157.

[8] Menzaghi C,Ereolino T,Di Paola R,et al.A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome.Diabetes,2002,51(7):2306-2312.

[9] Berthier MT, Houde A, Cote M,et al. Impact of adipo nectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men.J Lipid Res,2005,46(2):237-244.

[10] 杜鹏飞,徐敏,洪洁,等.脂联素基因多态性与胰岛素抵抗的相关性研究.中华糖尿病杂志,2004,12(6):393-396.

[11] Salmenniemi U.Zacharova J,Ruotsalainen E,et al.Association of adiponectin level and variants in the adiponectin gene with glucose metabolism, energy expenditure, and cytokines in offspring of type 2 diabetic patients. J Clin Endocrinol Metnb,2005,90(7):4216-4223.

[12] Ohashi K,Ouchi N,Kihara S,et al.Adiponectin l164T mutation is associated with the metabolic syndrome and coronary heart disease.J Am Coll Cardio1.2004,43(7):1195-200.

[13] Vimaleswaran KS, Radha V, Ramya K,et al.A novel association of a polymorphism in the first intron of adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia in Asian Indians.Hum Genet,2008,123(6):599-605.

[14] Patel S, Flyvbjerg A, Koza`kova` M, Frystyk J, Ibrahim IM, Petrie JR, Avery PJ, Ferrannini E, Walker M, the RISC Investigators. Variation in the ADIPOQ gene promoter is associated with carotid intima media thickness independent of plasma adiponectin levels in healthy subjects. Eur Heart J,2008,29:386-393. First published on December 15, 2007. doi:10.1093/eurheartj/ehm526.

[15] Walker M, Patel S,et al. Association between the C-11377G promoter variant of the ACDC gene and carot intima thickness in healthy subjects. Diabetologia,2006,49(suppll):212-213.

[16] Hoefle G, Muendlein A, Saely CH,et al.The -11377 C>G promoter variant of the adiponectin gene, prevalence of coronary atherosclerosis, and incidence of vascular events in men.Thromb Haemost,2007,97(3):451-457.

[17] Vasseur F, Helbecque N, Dina C,et al.Plasma concentrations of a novel adipose-specific protein, adiponectin, in type 2 diabetic patients.Arterioscl Thromb Vase Biol,2000,20:1595-1599.

[18] Sun H, Gong ZC, Yin JY,et al.The association of adiponectin allele 45T/G and -11377C/G polymorphisms with Type 2 diabetes and rosiglitazone response in Chinese patients.Br J Clin Pharmacol,2008,65(6):917-926.

[19] Ryu SY, Kim KS, Park J, Kang MG, Han MA,et al.The association between circulating inflammatory markers and metabolic syndromein Korean rural adults.J Prev Med Public Health,2008,41(6):413-418.

[20] Xydakist AM, Case CC, Jones PH,et al.adiponectin,imflammation,and the expression,of the metabolic syndrome in obese individuals:the impact of rapid eight 1oss through caloric restriction.Journal of Clinical Endocrinology & Metabolism,2004,89:2697- 2703.

[21] Hung J, McQuillan BM, Thompson PL,et al.Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity.Int J Obes (Lond),2008,32(5):772-779.

[22] Hotta K,Funahashi T,Bodkin NL,et al.Circulating congcentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.Diabetes,2001,50:1126-1133.

[23] Milan G,Granzotto M,Scarda A,et al.Resistin and adiponecin expression in visceral fat of obese rats:effect of weight loss.Obes Res,2002,10(11):1095-1103.

[24] Lele RD,Joshi SR,Gupte A.Association of adipocytokines(1eptin,adiponectin TNF-alpha).insulin and proinsulin with diabetes-theMumbai Obesity Project(MOP).J Assoc Physicians India,2006,54:689-696.

[25] Yang Ws,Lee WJ.Funhashi T,et al.Weight reduction increased plasma levels of an adipose- derived anti-inflammatory rotein.adiponectin.J Clin Endocrirol Metab,2001,86(8):815- 819.

[26] 王遂军,贾伟军,包玉倩,等.血清脂联素与肥胖的关系.中华内分泌代谢杂志,2005,21:36-38.

[27] Yamauchi T,Kanaon J,Waki H,et al.fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.Nat Med,2001,7:941-946.

[28]Berg AH, Combs TP , Du X , et al.The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.Nat Med,2001,7(8):947-953.

[29] Maeda N,Shimomura I,Kishida K.Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.Nat Med,2002,8(7):731-737.

[30] Yano W,Kubota N,Itoh S,et al.Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice.Endocr J,2008,55(3):515-522.

[31] Semple RK, Cochran EK, Soos MA,et al.Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance.Diabetes Care,2008,31(5):977-979.

[32] 陈蕾,项坤三,贾伟平,等.血清脂联素浓度与体脂分布及葡萄糖钳夹试验中胰岛素敏感性的关系.中华医学杂志,2005,85(21):1456-1459.

[33] Maeda N,Shimomura I,Kishida K,et al.Diet-induced iasulin resistance in mice lacking adiponectin/ACRP30.Nat Med,2002,8:731-737.

[34] Matsubara M,Maruoka S,Katayose S.Decreased plasma a adiponectin concentrations in women with dyslipidemia.J Clin Endocrinol Metab,2002,(6):2764- 2769.

[35] Dietrich R,Hermann B,Winfried M,et al.Adiponectin,risk of coronary heart disease and correlations with cardiovascular risk markers.Eur Heart J,2005,26:1640-1646.

[36] Marso SP, Mehta SK, Frutkin A,et al.Low adiponectin levels are associated with atherogenic dyslipidemia and lipid-rich plaque in nondiabetic coronary arteries.Diabetes Care, 2008,31(5):989-994.

[37] Mitsutake R, Miura S, Kawamura A, Saku K,et al.Are metabolic factors associated with coronary artery stenosis on MDCT.Circ J,2009,73(1):132-138.

[38] von Eynatten M, Hamann A, Twardella D,et al.Atherogenic dyslipidaemia but not total- and high-molecular weight adiponectin are associated with the prognostic outcome in patients with coronary heart disease.Eur Heart J,2008,29(10):1307-1315.

[39] Nomura S, Shouzu A, Omoto S,et al.Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus.Thromb Res,2008,122(1):39-45.

[40] Takagi T, Matsuda M, Abe M,et al.Effect of pravastatin on the development of diabetes and adiponectin production.Atherosclerosis,2008,196(1):114-121.

[41] Chu CH, Lee JK, Lam HC,et al.Atorvastatin does not affect insulin sensitivity and the adiponectin or leptin levels in hyperlipidemic Type 2 diabetes. Endocrinol Invest,2008,31(1):42-47.

[42] Hotta K,Funahashi T,Arita Y.Plasma concentrations of a novel,adipose-specific protein,adiponectin,in type 2 diabetic patients.Arterioscler Thromb Vase Biol,2000,20:1595-1599.

[43] 张木勋,李春蕊,王宏伟,等.2型糖尿病和肥胖症患者血浆脂联素与瘦素的相关性.中华糖尿病杂志,2004,12(4):261-262.

[44] Heidemann C, Sun Q, van Dam RM,et al.Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women.Ann Intern Med,2008,149(5):307-316.

[45] Yoon SJ, Lee HS, Lee SW,et al.The association between adiponectin and diabetes in the Korean population.Metabolism,2008,57(6):853-857.

[46] Jalovaara K, Santaniemi M, Timonen M,et al.Low serum adiponectin level as a predictor of impaired glucose regulation and type 2 diabetes mellitus in a middle-aged Finnish population.Metabolism,2008,57(8):1130-1134.

[47] Choi KM ,Lee J,Lee KW,et al.Serum adiponectin concentrations predict the developments of type 2 diabetes and the metabolic syndrome in elderly Koreans.Clin Endocrinol,2004,6l(1):75-80.

[48] Mather KJ, Funahashi T, Matsuzawa Y,et al.Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program.Diabetes,2008,57(4):980-986.

[49] Li HY, Chiu YF, Hwu CM,et al.The negative correlation between plasma adiponectin and blood pressure depends on obesity: a family-based association study in SAPPHIRe.Am J Hypertens,2008,21(4):471-476.

[50] Ebinc H, Ozkurt ZN, Ebinc FA,et al.Adiponectin and insulin resistance in obesity-related diseases .J Int Med Res,2008,36(1):71-79.

[51] Adamezad M,W iecek A,Funahashi T,et al.Dreasead plasma adiponectin concentration inpatients with essential hypertension.AM J Hypertens,2003,16:72-75.

[52] Shankar A, Marshall S, Li J,et al.The association between plasma adiponectin level and hypertension.Acta Cardiol,2008,63(2):160-165.

[53] Imatoh T, Miyazaki M, Momose Y,et al.Adiponectin levels associated with the development of hypertension: a prospective study.Hypertens Res,2008,31(2):229-233.

[54] Koji 0,Shinji K,Noriyuki O,et al.Adiponectin replenishment ameliorates obesity-related hypertension .Hypertension,2006,47:1108-1116.

[55] Cai XJ, Li CJ, Chen L,et al.A hypothesis: adiponectin mediates anti-atherosclerosis via adventitia-AMPK-iNOS pathway.Med Hypotheses,2008,70(5):1044-1047.

[56] Tsubakio Yamamoto K, Matsuura F, Koseki M,et al.Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages.Biochem Biophys Res Commun,2008, 375(3):390-394.

[57] Saely CH, Risch L, Hoefle G,et al.Low serum adiponectin is independently associated with both the metabolic syndrome and angiographically determined coronary atherosclerosis.Clin Chim Acta,2007,383(1-2):97-102.

[58] Bernhard I,Vitolds M,Andreas S,et al.Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis data from the SAPHIR study.Stroke,2005,36(12):2577-2582.

[59] Bang OY, Saver JL, Ovbiagele B,et al.Adiponectin levels in patients with intracranial atherosclerosis.Neurology,2007,68(22):1931-1937.

[60] Stamatis PE,Dimitrios IT,Aphrodite GT,et al.Plasma adiponectin levels and five-year survival after first-ever ischemic stroke.Stroke,2005,36(9):1915-1919.

[61] Lim S, Koo BK, Cho SW,et al.Association of adiponectin and resistin with cardiovascular events in Korean patients with type 2 diabetes: the Korean atherosclerosis study (KAS): a 42-month prospective study.Atherosclerosis,2008,196(1):398-404.

[62] Frystyk J,Berne C,Berglund L,et al.Serum adiponectin is a predictor of coronary heart disease:a population-based 10-year follow-up study in elderly men.Journal of Clinical Endocrinology&Metabolism,2007,49:531-538.

[63] Laughlin GA,Barrett-Connor E,May S,et al.Association of adiponectinwith coronary heart disease and mortality.American Journal of epidemiology,2006,10:1093.

[64] Cavusoglu E ,Ruwende C,Chopra V,et al.Adiponectin is an independent predictor of all-cause mortality,cardiac mortality,and myocardial infarction in patients presenting with chest pain.European heart journal,2006,27:2300-2309.

[65] Teoh H,Strauss MH,Szmitko PE,et al.Adiponectin and myocardial infarction:a paradox or a paradigm?European heart journal,2006,27:2266-2268.

[66] Wang Y, Lam K, Chan L, et al. Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem, 2006,281:16391-16400.

[67]Lin H, Kim J, Pocai A, et al. Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice. Diabetes. 2007,56: 1969-1976.

[68] Barnea M, Shamay A, Stark A, et al .A high-fat diet has a tissue-specific effect on adiponectin and related enzyme expression. Obesity. 2006,14: 2145-2153.

[69] Cammisotto P, Londono I, Gingras D, et al. Control of glycogen synthace through AdipoR1-AMPK pathway in renal distal tubules of normal and diabetic rats. Am J Physiol Renal Physiol, 2008,294:F881-F889.