脂联素与胰岛素抵抗和动脉粥样硬化的研究
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摘要
背景与目的:
近年来,随着世界各国社会经济的发展和居民生活水平的提高,糖尿病(diabetes mellitus, DM)的发病率及患病率逐年升高,而DM患者中有95%是2型糖尿病(type 2 diabetes mellitus, T2DM),DM及其心、脑血管合并症/并发症成为威胁人类健康的重大社会问题,引起各国政府、卫生部门以及广大医务工作者的关注和重视。
近20年来,我国DM患病率显著增加。1980年全国14省市30万人的流行病学调查结果显示,DM患病率为0.67%。1994年全国19省市21万人的调查显示,25～64岁年龄段DM的患病率为2.5%,糖调节受损(impaired glucose regulation, IGR)为3.2%,比1980年增加了近3倍。2002年调查了DM的流行情况,在18岁以上的人口中,DM患病率为2.6%,我国DM患病率在过去20年中上升了4倍。据国际糖尿病联盟(IDF)估计,中国DM患病人数仍在快速增长,2007年约为3980万,2025年预计将达到5930万。
冠心病(coronary heart disease, CHD)是DM的主要大血管合并症,据报道DM合并CHD者高达72.3%,约50%T2DM患者在诊断时已有CHD。而且DM本身又加速CHD的发展,2001年美国国家成人胆固醇教育计划第三次报告(NCEP-ATPⅢ)明确提出“DM是CHD等危症”。中华医学会糖尿病学分会2001年组织对京、津、沪、渝4城市10家医院住院DM患者并发症患病率调查,合并各种心血管并发症者高达93%,其中高血压占41.8%、CHD占25.1%、脑血管病占17.3%,约80%的DM患者死于心血管并发症,其中75%死于CHD,为非DM人群的2～4倍。因此从某种意义上讲,对DM的防治,自始至终其主要目的就是尽可能地预防和延缓CHD的发生,从而降低DM患者CHD死亡率。
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一种除外酒精和其它明确的损肝因素所致的、以弥漫性肝细胞大泡性脂肪变为主要特征的肝脏病变,单纯性脂肪肝及其演变的脂肪性肝炎和肝硬化。随着人们饮食结构的改变,近年来NAFLD已成为我国常见的慢性肝病之一。NAFLD与代谢综合征(metabolic syndrome, MS)关系十分密切,2003年美国临床内分泌医师学会(AACE)甚至将NAFLD列为MS的诊断条件之一。NAFLD不但与胰岛素抵抗(insulin resistance, IR)综合征相伴,也是IR的早期标志。如果把NAFLD的防治意义提高到预防IR早期形成的高度,定会把IR综合征及其相关疾病的发生、发展推迟。
IR是指胰岛素作用的靶器官对胰岛素作用的敏感性下降,即正常剂量的胰岛素产生低于正常生物学效应的一种状态。IR与十余种代谢疾病有关,这些疾病包括:中心性肥胖、糖代谢异常、T2DM、脂代谢紊乱(高甘油三酯血症和/或高密度脂蛋白降低)、高血压、微量白蛋白尿、CHD、NAFLD等,IR是这些疾病的共同发病基础。人们把这些以IR为基础的各种疾病的总和,称为IR综合征。随着对IR研究的不断深入,人们逐渐认识到IR不但是DM的重要发病机制,而且也是发生DM各种并发症的病理基础。目前已经有更多的研究表明,虽然严格控制血糖可以显著的降低眼睛、神经、肾脏并发症的发生率,但是不能阻挡并发症的发生和发展,尤其是心、脑血管并发症,这就预示着除了高血糖之外还有别的因素在侵蚀着DM患者的身体。IR的患者,大多数是肥胖者。近年来的研究证实,肥胖与IR是一对难舍难分的孪生姊妹。肥胖者,体内的脂肪细胞会分泌许多新的激素,如脂联素、抵抗素和瘦素等,这些激素"干扰"了细胞上的胰岛素受体及受体后一系列反应,影响对胰岛素的敏感性。同时,IR又会使人体产生高胰岛素血症,高胰岛素血症又反过来引起肥胖。
脂联素是一种新的脂肪细胞特异性蛋白,因其具有对DM组织的保护作用,成为目前的研究热点。虽然它在循环中的浓度较高,但它在肥胖患者体内的水平却低于消瘦者。除了与肥胖呈负相关外,在IR和T2DM中,脂联素水平也降低。内脏性肥胖是脂联素水平下降的独立的预报器。因此,MS的诸多特点都与脂联素呈负相关。脂联素水平的下降似乎先于T2DM的发展。给予脂联素后,血糖水平降低和胰岛素敏感性(insulin sensitivity, IS)增高。动物模型显示脂联素表达减少与一定程度的IR相关,这说明低脂联素血症在IR中的作用。研究证明脂联素可加速脂肪酸氧化,促进糖转运及降低肝糖输出,这些是脂联素提高IS的主要机制。血浆脂联素水平在CHD及其他大血管病变中明显降低,与心血管病变密切相关。脂联素可降低肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)刺激的黏附分子的表达,抑制外周单核细胞的生长和炎症因子的释放,具有保护内皮、抗炎、抗动脉粥样硬化(atherosclerosis, AS)的功能。致炎性的细胞因子,特别是TNF-α反过来可以降低脂联素水平。脂联素还可能是一种胰岛素的增敏剂,有望成为一种新的治疗IR的药物。
二甲双胍之所以能在诸多降糖药物中脱颖而出,完全得益于其全面的功效以及良好的安全性。第一,二甲双胍的降糖作用不是靠刺激胰岛素分泌,而是通过改善IR,增加机体对葡萄糖的利用、抑制肝糖原的产生来完成的。它不会加重胰岛β细胞的负担,也不会导致高胰岛素血症。第二,二甲双胍的降糖效果非常理想。第三,与其他降糖药物相比,二甲双胍在降糖的同时可有效控制体重。第四,具有心血管保护作用,二甲双胍是目前惟一有证据表明可以降低T2DM患者心血管并发症的降糖药物。有研究证明,二甲双胍除了能降低42%的DM相关死亡外,还可降低39%的心肌梗死风险和41%的脑卒中风险。第五,二甲双胍价格低廉,具有良好的性价比。
T2DM患者发生AS的机制与IR密切相关,NAFLD是IR的早期标志,而脂联素具有拮抗IR的作用,二甲双胍能够改善IR。本研究探讨二甲双胍是否可以通过改善IR来预防T2DM患者AS的发生发展,二甲双胍改善IR的机制是否与增加脂联素的表达有关,以及T2DM合并NAFLD患者血清脂联素与IR的关系。深入了解脂联素的作用机制,将对阐明与IR相关疾病的发病机制和脂联素作为肥胖、心血管疾病、DM之间纽带的确切机制提供理论依据,为与IR相关疾病的防治提供新的思路。
方法:
一、二甲双胍对DM大鼠脂联素的影响。用链脲佐菌素(STZ)和高热量饲料建立DM大鼠模型,并给予二甲双胍治疗,分为DM对照组(DM组)、二甲双胍低剂量组(Met-L, 100mg.kg-1.d-1)、二甲双胍高剂量组(Met-H, 156mg.kg-1.d-1),以健康SD大鼠作为正常对照组(NC组)。二甲双胍治疗4周后,处死大鼠,腹主动脉取血,测定空腹血糖(FBG)、甘油三酯(TG)、总胆固醇(TC)、血清空腹胰岛素(FINS)、TNF-α、脂联素;胰岛素抵抗程度判断使用HOMA胰岛素抵抗指数( HOMA-IR )表示,HOMA-IR=FBG×FINS/22.5;取肾周脂肪组织,用RT-PCR测定脂肪组织中的TNF-α和脂联素的表达,UVP-GDS 8000凝胶成像分析系统扫描图像并测定电泳条带的灰度,以目的基因(脂联素、TNF-α)与内参(β-actin)电泳条带灰度值的比值作数据分析。对大鼠的主动脉进行油红染色,观察动脉的变化。采用SPSS 12.0统计软件进行统计学处理,多样本均数比较用单因素方差分析(one-way ANOVA),各组间的两两比较用最小显著差法(LSD)分析,相关性分析采用Pearson相关分析,P<0.05为差异有统计学意义。
二、二甲双胍对T2DM患者脂联素及AS的影响。140例T2DM患者,年龄35～70岁,性别不限;新诊断或已确诊病程在1年以内;体重指数(BMI)19～35 kg/m2;半年内无酮症或其他应激情况;临床无心、脑、肾及外周血管AS疾病史及证据;超声测定颈总动脉内中膜厚度(CC-IMT)≤1.0 mm,且可视范围内无AS斑块形成,强化血糖、血压、血脂治疗,同时服用阿司匹林(100mg/d)。根据应用口服降糖药种类分为二甲双胍组(75例)和非二甲双胍组(65例),所有患者均未应用噻唑烷二酮类药物及胰岛素。记录强化治疗100周前后随访指标,测身高、体重,计算BMI;测腰围、臀围,计算腰臀比(WHR);测血压、FBG、糖负荷后2小时血糖(P2hBG)、糖化血红蛋白(HbA1C)、TG、TC、高密度脂蛋白胆固醇( HDL-C)、低密度脂蛋白胆固醇( LDL-C)、FINS、CC-IMT,计算HOMA-IR。以CC-IMT作为强化治疗后心血管是否获益的观测目标。采用SPSS 12.0统计软件进行统计分析,非正态分布的资料进行对数转换后分析。组间比较用成组t检验,配对设计用配对t检验;相关性分析用longistic多元回归分析。
三、T2DM合并NAFLD患者脂联素与IR关系的研究。选取30例T2DM合并NAFLD患者、30例T2DM无脂肪肝患者和30例健康志愿者作为对照(NC)组,测定身高、体重、腰围、臀围、血压、FBG、血脂、FINS和脂联素水平,计算BMI、WHR和HOMA-IR。采用SPSS 12.0统计软件进行统计学处理,多样本均数比较用单因素方差分析(one- way ANOVA),各组间的两两比较用最小显著差法(LSD)分析,相关性分析采用Pearson相关分析。
结果:
一、二甲双胍对DM大鼠脂联素的影响。DM组、Met-L组和Met-H组大鼠体重明显高于NC组(P<0.01或P<0.05),而Met-L组和Met-H组与DM组相比,体重下降,差异具有统计学意义(P<0.05)。DM组大鼠血FBG、TC、TG均明显高于NC组(P<0.01或P<0.05),但是FINS与NC组相比没有明显变化(P>0.05)。给予二甲双胍治疗,降低血糖(P<0.05)的同时,血脂水平也明显降低(P<0.05),而且随着剂量的增加,血糖、血脂下降幅度更大,而FINS始终没有明显变化(P>0.05)。DM组、Met-L组和Met-H组大鼠HOMA-IR明显高于NC组(P<0.05)。Met-L组和Met-H组与DM组相比,HOMA-IR显著下降低(P<0.05),而且随着剂量的增加,更有利于改善IR。
DM组TNF-α显著高于NC组(P<0.05),Met-L组和Met-H组与DM组相比,血清TNF-α减少(P<0.05),而且药物高剂量组低于低剂量组(P<0.05)。血清脂联素呈现出与TNF-α相反的变化,DM组低于NC组(P<0.05),给予二甲双胍治疗,血清脂联素浓度增加,但是Met-L组尚未达到统计学意义(P>0.05), Met-H组趋向于NC组,并且与DM组相比差异具有统计学意义(P<0.05)。
RT-PCR产物电泳后可见DM组大鼠脂肪组织脂联素mRNA表达明显减少(P<0.05),而TNF-αmRNA表达增加(P<0.05)。二甲双胍治疗使二者的表达异常有部分恢复,且高剂量作用强于低剂量。
HOMA-IR与脂联素水平呈显著负相关(r =-0.498,P<0.05),与TNF-α水平呈显著正相关(r = 0.35,P<0.05)。
各组大鼠动脉未见明显的粥样硬化斑块。
二、二甲双胍对T2DM患者脂联素及AS的影响。入组时两组患者的各项指标均无明显差异(P>0.05)。经过100周强化代谢控制后,与干预前相比,两组DBP、FBG、P2hBG、HbA1C、TG、TC、LDL-C均明显下降(P<0.05),而WHR、SBP均无变化(P>0.05);二甲双胍组的BMI、HOMA-IR和CC-IMT降低(P<0.05),HDL-C水平有所升高(P<0.05),非二甲双胍组的BMI、HOMA-IR、HDL-C和CC-IMT有变化趋势,但差异不显著(P>0.05);两组脂联素均明显升高(P<0.05)。强化代谢控制后,二甲双胍组的HOMA-IR和CC-IMT均较非二甲双胍组低(P<0.05);二甲双胍组的脂联素较非二甲双胍组高(P<0.05)。
相关性分析显示,CC-IMT与BM(Ir = 0.489, P<0.05)、TC(r = 0.429,P<0.05)、LDL-C(r=0.426, P<0.05)、HOMA-IR(r = 0.428, P<0.05)正相关,与脂联素呈负相关(r =-0.485, P<0.05)。
三、T2DM合并NAFLD患者脂联素与IR关系的研究。T2DM合并NAFLD组与T2DM无脂肪肝组患者BMI、WHR、SBP、DBP、FBG、FINS、TG、TC、HOMA-IR均高于NC组(P<0.05);T2DM合并NAFLD组BMI、WHR、FINS、TG、HOMA-IR高于T2DM无脂肪肝组(P<0.05),而SBP、DBP、FBG、TC与T2DM无脂肪肝组无差异(P>0.05)。
T2DM合并NAFLD组与T2DM无脂肪肝组血清脂联素低于NC组(P<0.05),T2DM合并NAFLD组血清脂联素较T2DM无脂肪肝组更低(P<0.05)。
logistic回归多因素分析结果显示,BMI、WHR、TG、脂联素与T2DM合并NAFLD发生IR密切相关,脂联素与T2DM合并NAFLD发生IR相关性更为密切(OR值= 3.59,P<0.01)。
结论:
一、二甲双胍的治疗改善IR的同时,也增加了血清和组织中脂联素的表达,二甲双胍改善IR的机制之一可能是通过增加脂联素的表达而获益。
二、二甲双胍可以降低T2DM患者的CC-IMT,可以预防T2DM患者发生AS。血清脂联素浓度与CC-IMT具有明显的负相关性,脂联素的抗IR和抗AS作用明显。
三、T2DM合并NAFLD患者血清脂联素水平降低,并与IR密切相关,脂联素可能在T2DM患者的NAFLD发生、发展中起重要的作用。
Background and objective
The incidence and morbidity of diabetes mellitus (DM) were increased in these years with the development of world economy and elevation of people’s life. DM becomes an important social problem to threaten people’s health. It invokes attention of governments, departments of health and medical workers all over the world. The morbidity of type 1 diabetes mellitus (T1DM) is far lower than that of type 2 diabetes mellitus (T2DM). The morbidity of T2DM in the earth was reased sharply in these years, which is the main reason for quick enhancement of the total of diabetic patients.
The morbidity of DM in our country was increased prominently. The epidemiological findings of 30 ten thousands persons in 14 provinces showed that the morbidity of DM was 0.67% in 1980. The findings of 21 ten thousands persons in 19 provinces indicated that the morbidity of DM was 2.5% and the morbidity of impaired glucose regulation (IGR) was 3.2% in 1994. The amount of diabetic patients in 1994 grew 3 times than that in 1980. The epidemiological results in 2002 revealed that the morbidity of DM was 2.6% in the population over 18 years old. The morbidity of DM mounted up 4 times in the past 20 years. IDF estimates that diabetic patients in China still grow swiftly. The amount of diabetic patients was 3980 ten thousands in 2007. And it will be 5930 ten thousands in 2025.
Coronary heart disease (CHD) is the major macrovascular complication of DM. 72.3 percent of diabetic patients were companied with CHD. 50 percent of type 2 diabetic patients were coupled with CHD at the beginning of diagnosis. DM accelerates the development of CHD. NCEP-ATPⅢput forward definitely in 2001 that DM was as dangerous as CHD. The findings of ten hospitals in Beijing, Tianjin, Shanghai and Chongqing in 2001 pointed out that 93 percent of diabetic patients incorporated various cardiovascular diseases. And 80 percent of diabetic patients died from cardiovascular diseases. So the aim to prevent and cure DM is to prevent and suspend the occurrence of CHD, which decreases consequently the mortality of CHD among diabetic patients.
Non-alcoholic fatty liver disease (NAFLD) is characterized with diffuse bulbous fatty changes of hepatic cells except for alcoholic and other definite causes damaging liver. It includes simple fatty liver disease, fatty hepatitis and cirrhosis. NAFLD becomes one of common chronic hepatic diseases in China with the modification of diets. NAFLD is related closely to metabolic syndrome (MS). AACE put NAFLD as one of diagnostic criteria of MS in 2003. NAFLD is not only companied with insulin resistant syndrome, but also is an early mark of insulin resistance (IR). Insulin resistant syndrome and its related diseases would be postponed if NAFLD was prevented.
IR means that target organs’sensitivity to insulin declines, which is a condition that normal amount of insulin can not produce normal biological effects. It is related to more than 10 metabolic diseases, which include central obesity, abnormal glycometabolism, T2DM, disturbing lipid metabolism, hypertension, microalbuminuria, CHD, NAFLD, and so on. The summation of these diseases are called insulin resistant syndrome because IR is the common basis of them. Researchers realize gradually that IR is not only the important pathogenesis but also the pathological foundation of diabetic complications. More and more researches show that although intensive glucose control can reduce the occurrences of ophthalmopathy, neuropathy and nephropathy, it can not stop the occurrence and development of macrovascular complications. So there are other factors acting on diabetic patients except for high blood glucose. Insulin resistant patients are usually obese. Adipose cells in obese persons secret many new hormones, such as adiponectin, resistin, leptin, and so on. All of these hormones influence the body sensitivity to insulin. IR results in hyperinsulinemia in the body. Meanwhile hyperinsulinemia causes obesity.
Adiponectin is a new specific protein of adipose cells. It is a study hot due to its protection for diabetic tissues. It is negatively correlated to obesity. Its level is decreased in insulin resistant patients and type 2 diabetic patients. Visceral obesity is an independent predictor of low adiponectin level. The characteristics of MS are negatively correlated to adiponectin. The decline of adiponectin level comes before the progress of T2DM. Blood glucose goes down and insulin sensitivity (IS) goes up after the patient is given adiponectin. Hypoadiponectinemia plays a role in IR, because low expression of adiponectin is relative to IR in animal models. Adiponectin speeds fatty acid oxidation, accelerates glucose transportation and heightens IS. So adiponectin can improve IS. Plasma adiponectin is obviously depressed in macrocardiological diseases. Adiponectin is loosely related to cardiovascular diseases. It has functions of protecting endothelial cells, anti-inflammation and anti-AS. It may be a kind of insulin sensitizer. It may be a new drug to cure IR.
Metformin has all-round efficacy and good safety. Firstly, it improves IR, increases utilization of glucose and inhibits production of hepatic glycogen. It doesn’t aggravate burden ofβcells in islet. It can not cause hyperinsulinemia. Secondly, it has perfect effect on reducing blood glucose. Thirdly, it reduces body weight. Fourthly, it has cardiovascular protection. It is the only one hypoglycemic drug with the proof to decrease cardiovascular complications of type 2 diabetic patients until now. It can depress risks of myocardial infarction and stroke. Fifthly, it has low price and good cost performance. The mechanism of AS is closely related to IR in type 2 diabetic patients. NAFLD is an early mark of IR. Adiponectin can counteract IR. Metformin can ameliorate IR. The research investigates whether metformin may increase expression of adiponectin, whether improvement of IR may prevent AS in type 2 diabetic patients, and the relationship between adiponectin and IR in type 2 diabetic patients accompanying with NAFLD. The deep study was made to see whether adiponectin would be a new thought for curing insulin resistant diseases.
Methods:
1. Effects of metformin on adiponectin in diabetic rats. Diabetic rats were induced by feeding fat rich food and injecting streptozotocin (25mg·kg-1).Then diabetic rats were fed with metformin. According to the dose of metformin, these rats were divided into three groups: metformin with low dose group (Met-L, 100mg.kg-1.d-1), metformin with high dose (Met-H, 156mg.kg-1.d-1), and diabetic rats without metformin (DM). Healthy SD rats were as normal control (NC). Rats were killed after 4 weeks and were taken blood in aorta abdominalis. Fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), fasting insulin (FINS), TNF-αand adiponectin were measured. IR index (HOMA-IR) was calculated. The expressions of TNF-αand adiponectin genes in perinephral adipose tissues were tested by RT-PCR. The scores for AP-lesion of aorta were evaluated according to the pathological degrees with oil red Ostaining, The pathologic changes was examined by hematoxylin and eosin (HE) staining.
2. Effects of metformin on adiponectin and AS in patients with T2DM. One hundred and forty patients with T2DM aged from 35 to 70 years old, with the course less than 1 year and without subclinical AS. All patients received 100-week intervention based on anti-platelet therapy integrated with intensive controls of blood glucose, blood lipid, blood pressure and body weight. According to the category of oral antidiabetic drug (OHA), the patients were divided into two groups: patients with metformin and patients without metformin. All patients did not use thiazolidinediones (TZDs) and insulin. Body mass index (BMI), waist-to-hip ratio (WHR), blood pressure (BP), FBG, post 2-hour blood glucose (P2hBG), glycated hemoglobin A1C (HbA1C), TG, TC, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), FINS and common carotid intima-media thickness (CC-IMT) were measured. Dynamic changes in all metabolic indicators were observed after 100-week intensive intervention. CC-IMT was an indicator for AS.
3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. There were three groups: T2DM patients with NAFLD, T2DM patients without fatty liver disease, and normal control. Body height, body weight, waist circumstance, hip circumstance, BP, FBG, blood lipid, FINS and adiponectin were measured. BMI, WHR and HOMA-IR were calculated.
Results:
1. Effects of metformin on adiponectin in diabetic rats. The body weights in DM group, Met-L group and Met-H group were significantly higher than that in NC group (P<0.01 or P<0.05). The body weights in Met-L group and Met-H group were significantly lower than that in DM group (P<0.05). FBG, TC and TG in DM group were higher than those in NC group (P<0.01 or P<0.05). While there was no significant change of FINS between DM group and NC group (P>0.05). Blood glucose and lipid were decreased significantly in Met-L group and Met-H group (P<0.05). And the changes were depended on the dose of metformin. While there was still no significant change of FINS (P>0.05). HOMA-IRs in DM group, Met-L group and Met-H group were higher than that in NC group (P<0.05). HOMA-IR in Met-L group and Met-H group were lower than that in DM group (P<0.05). The more the dose, the more the decline.
TNF-αin DM group was significantly higher than that in NC group (P<0.05). TNF-αin Met-L group and Met-H group were dropped compared with that in DM group (P<0.05). And TNF-αin Met-H group was lower than that in Met-L group (P<0.05). Adiponectin in DM group was significantly lower than that in NC group (P<0.05). Adiponectin in Met-H group was augmented compared with that in DM group (P<0.05), whose concentration was tended similar to that in NC group. Adiponectin in Met-H group was also fortified, while the change didn’t get statistical significance (P>0.05).
The expression of adiponectin mRNA in adipose tissue was decreased (P<0.05). The expression of TNF-αmRNA in adipose tissue was increased (P<0.05). Metformin can renovate partly abnormal expression of adiponectin and TNF-α. The more the dose, the stronger the action.
HOMA-IR was negatively related to adiponectin (r=-0.498, P<0.05). HOMA-IR was positively related to TNF-α(r = 0.35, P<0.05).
All rats had no atheromatous plaques.
2. Effects of metformin on adiponectin and AS in patients with T2DM.
There was no significant difference of all metabolic indicators between both groups before intensive intervention (P> 0.05). Diastolic blood pressure (DBP), FBG, P2hBG, HbA1C, TG, TC and LDL-C were significantly decreased in both groups after intensive intervention for 100 weeks (P<0.05). There was no significance of WHR and systolic blood pressure (SBP) in both groups after intensive intervention (P> 0.05). BMI, HOMA-IR and CC-IMT in metformin group were declined after intensive intervention (P<0.05). While HDL-C were raised (P<0.05). BMI, HOMA-IR, HDL-C and CC-IMT were varied tendency after intensive control. But the changes were not significant between pre- and post-intensive control (P> 0.05). Adiponectins in both groups were heightened after intensive control (P<0.05). HOMA-IR and CC-IMT in metformin group were lower than that in non-metformin group after intensive control (P<0.05). Adiponectin in metformin group was higher than that in non-metformin group (P<0.05).
Correlative analysis showed that CC-IMT was positively related to BMI (r = 0.489, P<0.05), TC (r = 0.429, P<0.05), LDL-C (r = 0.426, P<0.05), HOMA-IR (r = 0.428, P < 0.05). CC-IMT was negatively related to adiponectin (r = -0.485, P<0.05).
3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. BMI, WHR, SBP, DBP, FBG, FINS, TG, TC and HOMA-IR in both groups of T2DM with NAFLD and T2DM without fatty liver disease were higher than those in NC group (P<0.05). BMI, WHR, FINS, TG and HOMA-IR in the group of T2DM with NAFLD were higher than those in the group of T2DM without fatty liver disease (P<0.05). There was no significant difference of SBP, DBP, FBG and TC between both groups of T2DM with NAFLD and T2DM without fatty liver disease (P>0.05).
Serum adiponectins in both groups of T2DM with NAFLD and T2DM without fatty liver disease were lower than that in NC group (P<0.05). Serum adiponectin in the group of T2DM with NAFLD was lower than that in the group of T2DM without fatty liver disease (P<0.05).
Logistic regression multiple factor analysis showed that BMI, WHR, TG and adiponectin were correlated to IR in type 2 diabetic patients with NAFLD. Adiponectin was more closely related to IR than others in type 2 diabetic patients with NAFLD.
Conclusions:
1. Metformin can ameliorate IR. Meanwhile it can increase expression of adiponectin in serum and fatty tissue. One of mechanisms of metformin improving IR may be by way of enhancing expression of adiponectin.
2. Metformin can decrease CC-IMT of type 2 diabetic patients. So it can prevent type 2 diabetic patients from AS. The concentration of serum adiponectin is negatively correlated to CC-IMT. Adiponectin plays an evident role in anti-IR and anti-AS.
3. The level of serum adiponectin was dropped in type 2 diabetic patients with NAFLD. Adiponectin is closely related to IR. Adiponectin may have important affect on the occurrence and development of NAFLD in type 2 diabetic patients.
近年来,随着世界各国社会经济的发展和居民生活水平的提高,糖尿病(diabetes mellitus, DM)的发病率及患病率逐年升高,而DM患者中有95%是2型糖尿病(type 2 diabetes mellitus, T2DM),DM及其心、脑血管合并症/并发症成为威胁人类健康的重大社会问题,引起各国政府、卫生部门以及广大医务工作者的关注和重视。
近20年来,我国DM患病率显著增加。1980年全国14省市30万人的流行病学调查结果显示,DM患病率为0.67%。1994年全国19省市21万人的调查显示,25～64岁年龄段DM的患病率为2.5%,糖调节受损(impaired glucose regulation, IGR)为3.2%,比1980年增加了近3倍。2002年调查了DM的流行情况,在18岁以上的人口中,DM患病率为2.6%,我国DM患病率在过去20年中上升了4倍。据国际糖尿病联盟(IDF)估计,中国DM患病人数仍在快速增长,2007年约为3980万,2025年预计将达到5930万。
冠心病(coronary heart disease, CHD)是DM的主要大血管合并症,据报道DM合并CHD者高达72.3%,约50%T2DM患者在诊断时已有CHD。而且DM本身又加速CHD的发展,2001年美国国家成人胆固醇教育计划第三次报告(NCEP-ATPⅢ)明确提出“DM是CHD等危症”。中华医学会糖尿病学分会2001年组织对京、津、沪、渝4城市10家医院住院DM患者并发症患病率调查,合并各种心血管并发症者高达93%,其中高血压占41.8%、CHD占25.1%、脑血管病占17.3%,约80%的DM患者死于心血管并发症,其中75%死于CHD,为非DM人群的2～4倍。因此从某种意义上讲,对DM的防治,自始至终其主要目的就是尽可能地预防和延缓CHD的发生,从而降低DM患者CHD死亡率。
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一种除外酒精和其它明确的损肝因素所致的、以弥漫性肝细胞大泡性脂肪变为主要特征的肝脏病变,单纯性脂肪肝及其演变的脂肪性肝炎和肝硬化。随着人们饮食结构的改变,近年来NAFLD已成为我国常见的慢性肝病之一。NAFLD与代谢综合征(metabolic syndrome, MS)关系十分密切,2003年美国临床内分泌医师学会(AACE)甚至将NAFLD列为MS的诊断条件之一。NAFLD不但与胰岛素抵抗(insulin resistance, IR)综合征相伴,也是IR的早期标志。如果把NAFLD的防治意义提高到预防IR早期形成的高度,定会把IR综合征及其相关疾病的发生、发展推迟。
IR是指胰岛素作用的靶器官对胰岛素作用的敏感性下降,即正常剂量的胰岛素产生低于正常生物学效应的一种状态。IR与十余种代谢疾病有关,这些疾病包括:中心性肥胖、糖代谢异常、T2DM、脂代谢紊乱(高甘油三酯血症和/或高密度脂蛋白降低)、高血压、微量白蛋白尿、CHD、NAFLD等,IR是这些疾病的共同发病基础。人们把这些以IR为基础的各种疾病的总和,称为IR综合征。随着对IR研究的不断深入,人们逐渐认识到IR不但是DM的重要发病机制,而且也是发生DM各种并发症的病理基础。目前已经有更多的研究表明,虽然严格控制血糖可以显著的降低眼睛、神经、肾脏并发症的发生率,但是不能阻挡并发症的发生和发展,尤其是心、脑血管并发症,这就预示着除了高血糖之外还有别的因素在侵蚀着DM患者的身体。IR的患者,大多数是肥胖者。近年来的研究证实,肥胖与IR是一对难舍难分的孪生姊妹。肥胖者,体内的脂肪细胞会分泌许多新的激素,如脂联素、抵抗素和瘦素等,这些激素"干扰"了细胞上的胰岛素受体及受体后一系列反应,影响对胰岛素的敏感性。同时,IR又会使人体产生高胰岛素血症,高胰岛素血症又反过来引起肥胖。
脂联素是一种新的脂肪细胞特异性蛋白,因其具有对DM组织的保护作用,成为目前的研究热点。虽然它在循环中的浓度较高,但它在肥胖患者体内的水平却低于消瘦者。除了与肥胖呈负相关外,在IR和T2DM中,脂联素水平也降低。内脏性肥胖是脂联素水平下降的独立的预报器。因此,MS的诸多特点都与脂联素呈负相关。脂联素水平的下降似乎先于T2DM的发展。给予脂联素后,血糖水平降低和胰岛素敏感性(insulin sensitivity, IS)增高。动物模型显示脂联素表达减少与一定程度的IR相关,这说明低脂联素血症在IR中的作用。研究证明脂联素可加速脂肪酸氧化,促进糖转运及降低肝糖输出,这些是脂联素提高IS的主要机制。血浆脂联素水平在CHD及其他大血管病变中明显降低,与心血管病变密切相关。脂联素可降低肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)刺激的黏附分子的表达,抑制外周单核细胞的生长和炎症因子的释放,具有保护内皮、抗炎、抗动脉粥样硬化(atherosclerosis, AS)的功能。致炎性的细胞因子,特别是TNF-α反过来可以降低脂联素水平。脂联素还可能是一种胰岛素的增敏剂,有望成为一种新的治疗IR的药物。
二甲双胍之所以能在诸多降糖药物中脱颖而出,完全得益于其全面的功效以及良好的安全性。第一,二甲双胍的降糖作用不是靠刺激胰岛素分泌,而是通过改善IR,增加机体对葡萄糖的利用、抑制肝糖原的产生来完成的。它不会加重胰岛β细胞的负担,也不会导致高胰岛素血症。第二,二甲双胍的降糖效果非常理想。第三,与其他降糖药物相比,二甲双胍在降糖的同时可有效控制体重。第四,具有心血管保护作用,二甲双胍是目前惟一有证据表明可以降低T2DM患者心血管并发症的降糖药物。有研究证明,二甲双胍除了能降低42%的DM相关死亡外,还可降低39%的心肌梗死风险和41%的脑卒中风险。第五,二甲双胍价格低廉,具有良好的性价比。
T2DM患者发生AS的机制与IR密切相关,NAFLD是IR的早期标志,而脂联素具有拮抗IR的作用,二甲双胍能够改善IR。本研究探讨二甲双胍是否可以通过改善IR来预防T2DM患者AS的发生发展,二甲双胍改善IR的机制是否与增加脂联素的表达有关,以及T2DM合并NAFLD患者血清脂联素与IR的关系。深入了解脂联素的作用机制,将对阐明与IR相关疾病的发病机制和脂联素作为肥胖、心血管疾病、DM之间纽带的确切机制提供理论依据,为与IR相关疾病的防治提供新的思路。
方法:
一、二甲双胍对DM大鼠脂联素的影响。用链脲佐菌素(STZ)和高热量饲料建立DM大鼠模型,并给予二甲双胍治疗,分为DM对照组(DM组)、二甲双胍低剂量组(Met-L, 100mg.kg-1.d-1)、二甲双胍高剂量组(Met-H, 156mg.kg-1.d-1),以健康SD大鼠作为正常对照组(NC组)。二甲双胍治疗4周后,处死大鼠,腹主动脉取血,测定空腹血糖(FBG)、甘油三酯(TG)、总胆固醇(TC)、血清空腹胰岛素(FINS)、TNF-α、脂联素;胰岛素抵抗程度判断使用HOMA胰岛素抵抗指数( HOMA-IR )表示,HOMA-IR=FBG×FINS/22.5;取肾周脂肪组织,用RT-PCR测定脂肪组织中的TNF-α和脂联素的表达,UVP-GDS 8000凝胶成像分析系统扫描图像并测定电泳条带的灰度,以目的基因(脂联素、TNF-α)与内参(β-actin)电泳条带灰度值的比值作数据分析。对大鼠的主动脉进行油红染色,观察动脉的变化。采用SPSS 12.0统计软件进行统计学处理,多样本均数比较用单因素方差分析(one-way ANOVA),各组间的两两比较用最小显著差法(LSD)分析,相关性分析采用Pearson相关分析,P<0.05为差异有统计学意义。
二、二甲双胍对T2DM患者脂联素及AS的影响。140例T2DM患者,年龄35～70岁,性别不限;新诊断或已确诊病程在1年以内;体重指数(BMI)19～35 kg/m2;半年内无酮症或其他应激情况;临床无心、脑、肾及外周血管AS疾病史及证据;超声测定颈总动脉内中膜厚度(CC-IMT)≤1.0 mm,且可视范围内无AS斑块形成,强化血糖、血压、血脂治疗,同时服用阿司匹林(100mg/d)。根据应用口服降糖药种类分为二甲双胍组(75例)和非二甲双胍组(65例),所有患者均未应用噻唑烷二酮类药物及胰岛素。记录强化治疗100周前后随访指标,测身高、体重,计算BMI;测腰围、臀围,计算腰臀比(WHR);测血压、FBG、糖负荷后2小时血糖(P2hBG)、糖化血红蛋白(HbA1C)、TG、TC、高密度脂蛋白胆固醇( HDL-C)、低密度脂蛋白胆固醇( LDL-C)、FINS、CC-IMT,计算HOMA-IR。以CC-IMT作为强化治疗后心血管是否获益的观测目标。采用SPSS 12.0统计软件进行统计分析,非正态分布的资料进行对数转换后分析。组间比较用成组t检验,配对设计用配对t检验;相关性分析用longistic多元回归分析。
三、T2DM合并NAFLD患者脂联素与IR关系的研究。选取30例T2DM合并NAFLD患者、30例T2DM无脂肪肝患者和30例健康志愿者作为对照(NC)组,测定身高、体重、腰围、臀围、血压、FBG、血脂、FINS和脂联素水平,计算BMI、WHR和HOMA-IR。采用SPSS 12.0统计软件进行统计学处理,多样本均数比较用单因素方差分析(one- way ANOVA),各组间的两两比较用最小显著差法(LSD)分析,相关性分析采用Pearson相关分析。
结果:
一、二甲双胍对DM大鼠脂联素的影响。DM组、Met-L组和Met-H组大鼠体重明显高于NC组(P<0.01或P<0.05),而Met-L组和Met-H组与DM组相比,体重下降,差异具有统计学意义(P<0.05)。DM组大鼠血FBG、TC、TG均明显高于NC组(P<0.01或P<0.05),但是FINS与NC组相比没有明显变化(P>0.05)。给予二甲双胍治疗,降低血糖(P<0.05)的同时,血脂水平也明显降低(P<0.05),而且随着剂量的增加,血糖、血脂下降幅度更大,而FINS始终没有明显变化(P>0.05)。DM组、Met-L组和Met-H组大鼠HOMA-IR明显高于NC组(P<0.05)。Met-L组和Met-H组与DM组相比,HOMA-IR显著下降低(P<0.05),而且随着剂量的增加,更有利于改善IR。
DM组TNF-α显著高于NC组(P<0.05),Met-L组和Met-H组与DM组相比,血清TNF-α减少(P<0.05),而且药物高剂量组低于低剂量组(P<0.05)。血清脂联素呈现出与TNF-α相反的变化,DM组低于NC组(P<0.05),给予二甲双胍治疗,血清脂联素浓度增加,但是Met-L组尚未达到统计学意义(P>0.05), Met-H组趋向于NC组,并且与DM组相比差异具有统计学意义(P<0.05)。
RT-PCR产物电泳后可见DM组大鼠脂肪组织脂联素mRNA表达明显减少(P<0.05),而TNF-αmRNA表达增加(P<0.05)。二甲双胍治疗使二者的表达异常有部分恢复,且高剂量作用强于低剂量。
HOMA-IR与脂联素水平呈显著负相关(r =-0.498,P<0.05),与TNF-α水平呈显著正相关(r = 0.35,P<0.05)。
各组大鼠动脉未见明显的粥样硬化斑块。
二、二甲双胍对T2DM患者脂联素及AS的影响。入组时两组患者的各项指标均无明显差异(P>0.05)。经过100周强化代谢控制后,与干预前相比,两组DBP、FBG、P2hBG、HbA1C、TG、TC、LDL-C均明显下降(P<0.05),而WHR、SBP均无变化(P>0.05);二甲双胍组的BMI、HOMA-IR和CC-IMT降低(P<0.05),HDL-C水平有所升高(P<0.05),非二甲双胍组的BMI、HOMA-IR、HDL-C和CC-IMT有变化趋势,但差异不显著(P>0.05);两组脂联素均明显升高(P<0.05)。强化代谢控制后,二甲双胍组的HOMA-IR和CC-IMT均较非二甲双胍组低(P<0.05);二甲双胍组的脂联素较非二甲双胍组高(P<0.05)。
相关性分析显示,CC-IMT与BM(Ir = 0.489, P<0.05)、TC(r = 0.429,P<0.05)、LDL-C(r=0.426, P<0.05)、HOMA-IR(r = 0.428, P<0.05)正相关,与脂联素呈负相关(r =-0.485, P<0.05)。
三、T2DM合并NAFLD患者脂联素与IR关系的研究。T2DM合并NAFLD组与T2DM无脂肪肝组患者BMI、WHR、SBP、DBP、FBG、FINS、TG、TC、HOMA-IR均高于NC组(P<0.05);T2DM合并NAFLD组BMI、WHR、FINS、TG、HOMA-IR高于T2DM无脂肪肝组(P<0.05),而SBP、DBP、FBG、TC与T2DM无脂肪肝组无差异(P>0.05)。
T2DM合并NAFLD组与T2DM无脂肪肝组血清脂联素低于NC组(P<0.05),T2DM合并NAFLD组血清脂联素较T2DM无脂肪肝组更低(P<0.05)。
logistic回归多因素分析结果显示,BMI、WHR、TG、脂联素与T2DM合并NAFLD发生IR密切相关,脂联素与T2DM合并NAFLD发生IR相关性更为密切(OR值= 3.59,P<0.01)。
结论:
一、二甲双胍的治疗改善IR的同时,也增加了血清和组织中脂联素的表达,二甲双胍改善IR的机制之一可能是通过增加脂联素的表达而获益。
二、二甲双胍可以降低T2DM患者的CC-IMT,可以预防T2DM患者发生AS。血清脂联素浓度与CC-IMT具有明显的负相关性,脂联素的抗IR和抗AS作用明显。
三、T2DM合并NAFLD患者血清脂联素水平降低,并与IR密切相关,脂联素可能在T2DM患者的NAFLD发生、发展中起重要的作用。
Background and objective
The incidence and morbidity of diabetes mellitus (DM) were increased in these years with the development of world economy and elevation of people’s life. DM becomes an important social problem to threaten people’s health. It invokes attention of governments, departments of health and medical workers all over the world. The morbidity of type 1 diabetes mellitus (T1DM) is far lower than that of type 2 diabetes mellitus (T2DM). The morbidity of T2DM in the earth was reased sharply in these years, which is the main reason for quick enhancement of the total of diabetic patients.
The morbidity of DM in our country was increased prominently. The epidemiological findings of 30 ten thousands persons in 14 provinces showed that the morbidity of DM was 0.67% in 1980. The findings of 21 ten thousands persons in 19 provinces indicated that the morbidity of DM was 2.5% and the morbidity of impaired glucose regulation (IGR) was 3.2% in 1994. The amount of diabetic patients in 1994 grew 3 times than that in 1980. The epidemiological results in 2002 revealed that the morbidity of DM was 2.6% in the population over 18 years old. The morbidity of DM mounted up 4 times in the past 20 years. IDF estimates that diabetic patients in China still grow swiftly. The amount of diabetic patients was 3980 ten thousands in 2007. And it will be 5930 ten thousands in 2025.
Coronary heart disease (CHD) is the major macrovascular complication of DM. 72.3 percent of diabetic patients were companied with CHD. 50 percent of type 2 diabetic patients were coupled with CHD at the beginning of diagnosis. DM accelerates the development of CHD. NCEP-ATPⅢput forward definitely in 2001 that DM was as dangerous as CHD. The findings of ten hospitals in Beijing, Tianjin, Shanghai and Chongqing in 2001 pointed out that 93 percent of diabetic patients incorporated various cardiovascular diseases. And 80 percent of diabetic patients died from cardiovascular diseases. So the aim to prevent and cure DM is to prevent and suspend the occurrence of CHD, which decreases consequently the mortality of CHD among diabetic patients.
Non-alcoholic fatty liver disease (NAFLD) is characterized with diffuse bulbous fatty changes of hepatic cells except for alcoholic and other definite causes damaging liver. It includes simple fatty liver disease, fatty hepatitis and cirrhosis. NAFLD becomes one of common chronic hepatic diseases in China with the modification of diets. NAFLD is related closely to metabolic syndrome (MS). AACE put NAFLD as one of diagnostic criteria of MS in 2003. NAFLD is not only companied with insulin resistant syndrome, but also is an early mark of insulin resistance (IR). Insulin resistant syndrome and its related diseases would be postponed if NAFLD was prevented.
IR means that target organs’sensitivity to insulin declines, which is a condition that normal amount of insulin can not produce normal biological effects. It is related to more than 10 metabolic diseases, which include central obesity, abnormal glycometabolism, T2DM, disturbing lipid metabolism, hypertension, microalbuminuria, CHD, NAFLD, and so on. The summation of these diseases are called insulin resistant syndrome because IR is the common basis of them. Researchers realize gradually that IR is not only the important pathogenesis but also the pathological foundation of diabetic complications. More and more researches show that although intensive glucose control can reduce the occurrences of ophthalmopathy, neuropathy and nephropathy, it can not stop the occurrence and development of macrovascular complications. So there are other factors acting on diabetic patients except for high blood glucose. Insulin resistant patients are usually obese. Adipose cells in obese persons secret many new hormones, such as adiponectin, resistin, leptin, and so on. All of these hormones influence the body sensitivity to insulin. IR results in hyperinsulinemia in the body. Meanwhile hyperinsulinemia causes obesity.
Adiponectin is a new specific protein of adipose cells. It is a study hot due to its protection for diabetic tissues. It is negatively correlated to obesity. Its level is decreased in insulin resistant patients and type 2 diabetic patients. Visceral obesity is an independent predictor of low adiponectin level. The characteristics of MS are negatively correlated to adiponectin. The decline of adiponectin level comes before the progress of T2DM. Blood glucose goes down and insulin sensitivity (IS) goes up after the patient is given adiponectin. Hypoadiponectinemia plays a role in IR, because low expression of adiponectin is relative to IR in animal models. Adiponectin speeds fatty acid oxidation, accelerates glucose transportation and heightens IS. So adiponectin can improve IS. Plasma adiponectin is obviously depressed in macrocardiological diseases. Adiponectin is loosely related to cardiovascular diseases. It has functions of protecting endothelial cells, anti-inflammation and anti-AS. It may be a kind of insulin sensitizer. It may be a new drug to cure IR.
Metformin has all-round efficacy and good safety. Firstly, it improves IR, increases utilization of glucose and inhibits production of hepatic glycogen. It doesn’t aggravate burden ofβcells in islet. It can not cause hyperinsulinemia. Secondly, it has perfect effect on reducing blood glucose. Thirdly, it reduces body weight. Fourthly, it has cardiovascular protection. It is the only one hypoglycemic drug with the proof to decrease cardiovascular complications of type 2 diabetic patients until now. It can depress risks of myocardial infarction and stroke. Fifthly, it has low price and good cost performance. The mechanism of AS is closely related to IR in type 2 diabetic patients. NAFLD is an early mark of IR. Adiponectin can counteract IR. Metformin can ameliorate IR. The research investigates whether metformin may increase expression of adiponectin, whether improvement of IR may prevent AS in type 2 diabetic patients, and the relationship between adiponectin and IR in type 2 diabetic patients accompanying with NAFLD. The deep study was made to see whether adiponectin would be a new thought for curing insulin resistant diseases.
Methods:
1. Effects of metformin on adiponectin in diabetic rats. Diabetic rats were induced by feeding fat rich food and injecting streptozotocin (25mg·kg-1).Then diabetic rats were fed with metformin. According to the dose of metformin, these rats were divided into three groups: metformin with low dose group (Met-L, 100mg.kg-1.d-1), metformin with high dose (Met-H, 156mg.kg-1.d-1), and diabetic rats without metformin (DM). Healthy SD rats were as normal control (NC). Rats were killed after 4 weeks and were taken blood in aorta abdominalis. Fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), fasting insulin (FINS), TNF-αand adiponectin were measured. IR index (HOMA-IR) was calculated. The expressions of TNF-αand adiponectin genes in perinephral adipose tissues were tested by RT-PCR. The scores for AP-lesion of aorta were evaluated according to the pathological degrees with oil red Ostaining, The pathologic changes was examined by hematoxylin and eosin (HE) staining.
2. Effects of metformin on adiponectin and AS in patients with T2DM. One hundred and forty patients with T2DM aged from 35 to 70 years old, with the course less than 1 year and without subclinical AS. All patients received 100-week intervention based on anti-platelet therapy integrated with intensive controls of blood glucose, blood lipid, blood pressure and body weight. According to the category of oral antidiabetic drug (OHA), the patients were divided into two groups: patients with metformin and patients without metformin. All patients did not use thiazolidinediones (TZDs) and insulin. Body mass index (BMI), waist-to-hip ratio (WHR), blood pressure (BP), FBG, post 2-hour blood glucose (P2hBG), glycated hemoglobin A1C (HbA1C), TG, TC, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), FINS and common carotid intima-media thickness (CC-IMT) were measured. Dynamic changes in all metabolic indicators were observed after 100-week intensive intervention. CC-IMT was an indicator for AS.
3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. There were three groups: T2DM patients with NAFLD, T2DM patients without fatty liver disease, and normal control. Body height, body weight, waist circumstance, hip circumstance, BP, FBG, blood lipid, FINS and adiponectin were measured. BMI, WHR and HOMA-IR were calculated.
Results:
1. Effects of metformin on adiponectin in diabetic rats. The body weights in DM group, Met-L group and Met-H group were significantly higher than that in NC group (P<0.01 or P<0.05). The body weights in Met-L group and Met-H group were significantly lower than that in DM group (P<0.05). FBG, TC and TG in DM group were higher than those in NC group (P<0.01 or P<0.05). While there was no significant change of FINS between DM group and NC group (P>0.05). Blood glucose and lipid were decreased significantly in Met-L group and Met-H group (P<0.05). And the changes were depended on the dose of metformin. While there was still no significant change of FINS (P>0.05). HOMA-IRs in DM group, Met-L group and Met-H group were higher than that in NC group (P<0.05). HOMA-IR in Met-L group and Met-H group were lower than that in DM group (P<0.05). The more the dose, the more the decline.
TNF-αin DM group was significantly higher than that in NC group (P<0.05). TNF-αin Met-L group and Met-H group were dropped compared with that in DM group (P<0.05). And TNF-αin Met-H group was lower than that in Met-L group (P<0.05). Adiponectin in DM group was significantly lower than that in NC group (P<0.05). Adiponectin in Met-H group was augmented compared with that in DM group (P<0.05), whose concentration was tended similar to that in NC group. Adiponectin in Met-H group was also fortified, while the change didn’t get statistical significance (P>0.05).
The expression of adiponectin mRNA in adipose tissue was decreased (P<0.05). The expression of TNF-αmRNA in adipose tissue was increased (P<0.05). Metformin can renovate partly abnormal expression of adiponectin and TNF-α. The more the dose, the stronger the action.
HOMA-IR was negatively related to adiponectin (r=-0.498, P<0.05). HOMA-IR was positively related to TNF-α(r = 0.35, P<0.05).
All rats had no atheromatous plaques.
2. Effects of metformin on adiponectin and AS in patients with T2DM.
There was no significant difference of all metabolic indicators between both groups before intensive intervention (P> 0.05). Diastolic blood pressure (DBP), FBG, P2hBG, HbA1C, TG, TC and LDL-C were significantly decreased in both groups after intensive intervention for 100 weeks (P<0.05). There was no significance of WHR and systolic blood pressure (SBP) in both groups after intensive intervention (P> 0.05). BMI, HOMA-IR and CC-IMT in metformin group were declined after intensive intervention (P<0.05). While HDL-C were raised (P<0.05). BMI, HOMA-IR, HDL-C and CC-IMT were varied tendency after intensive control. But the changes were not significant between pre- and post-intensive control (P> 0.05). Adiponectins in both groups were heightened after intensive control (P<0.05). HOMA-IR and CC-IMT in metformin group were lower than that in non-metformin group after intensive control (P<0.05). Adiponectin in metformin group was higher than that in non-metformin group (P<0.05).
Correlative analysis showed that CC-IMT was positively related to BMI (r = 0.489, P<0.05), TC (r = 0.429, P<0.05), LDL-C (r = 0.426, P<0.05), HOMA-IR (r = 0.428, P < 0.05). CC-IMT was negatively related to adiponectin (r = -0.485, P<0.05).
3. Association of serum adiponectin with insulin resistance in type 2 diabetic patients with NAFLD. BMI, WHR, SBP, DBP, FBG, FINS, TG, TC and HOMA-IR in both groups of T2DM with NAFLD and T2DM without fatty liver disease were higher than those in NC group (P<0.05). BMI, WHR, FINS, TG and HOMA-IR in the group of T2DM with NAFLD were higher than those in the group of T2DM without fatty liver disease (P<0.05). There was no significant difference of SBP, DBP, FBG and TC between both groups of T2DM with NAFLD and T2DM without fatty liver disease (P>0.05).
Serum adiponectins in both groups of T2DM with NAFLD and T2DM without fatty liver disease were lower than that in NC group (P<0.05). Serum adiponectin in the group of T2DM with NAFLD was lower than that in the group of T2DM without fatty liver disease (P<0.05).
Logistic regression multiple factor analysis showed that BMI, WHR, TG and adiponectin were correlated to IR in type 2 diabetic patients with NAFLD. Adiponectin was more closely related to IR than others in type 2 diabetic patients with NAFLD.
Conclusions:
1. Metformin can ameliorate IR. Meanwhile it can increase expression of adiponectin in serum and fatty tissue. One of mechanisms of metformin improving IR may be by way of enhancing expression of adiponectin.
2. Metformin can decrease CC-IMT of type 2 diabetic patients. So it can prevent type 2 diabetic patients from AS. The concentration of serum adiponectin is negatively correlated to CC-IMT. Adiponectin plays an evident role in anti-IR and anti-AS.
3. The level of serum adiponectin was dropped in type 2 diabetic patients with NAFLD. Adiponectin is closely related to IR. Adiponectin may have important affect on the occurrence and development of NAFLD in type 2 diabetic patients.
引文
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