新脂肪细胞因子视黄醇结合蛋白4与肥胖及脂代谢的关系及机制研究_图文

1、上海交通大学博士学位论文新脂肪细胞因子视黄醇结合蛋白4与肥胖及脂代谢的关系及机制研究姓名：吴海娅申请学位级别：博士专业：内分泌代谢学指导教师：贾伟平20070501上海交通大学医学院2004级博士研究生学位论文主要符号和缩略语说明英文缩写 英文全称 中文译名ALT alanine aminotransferase 谷丙转氨酶APN adiponectin 脂联素BMI bodymass index 体重指数FPGfasting plasma glucose 空腹血糖 FFAfree fatty acid 游离脂肪酸 FINSfasting insulin 空腹胰岛素 GLUT4glucose

2、transporter 4 葡萄糖转运子4 GT-glutamyltransferase 谷氨酰转肽酶 HDL-C highdensity lipoprotein cholesterol 高密度脂蛋白胆固醇 HbA1c Glycated Hemoglobin A1c糖化血红蛋白 NCnormal control 正常对照 NGTnormal glucose tolerance 正常糖耐量 NWnormal weight 正常体重 LDL-C lowdensity lipoprotein cholesterol 低密度脂蛋白胆固醇 PPAR peroxisomeproliferators act

3、ivated receptor 过氧化物酶体增殖子 激活受体 RBP4 retinolbinding protein 4 视黄醇结合蛋白4 RT-PCRreverse transcription PCR 反转录PCR SD ratSprague-Dawley rat SD 大鼠 TCtotle cholesterol 总胆固醇 T2DM type2 diabetes mellitus 2型糖尿病 TGtriglyceride 甘油三脂19上海交通大学学位论文版权使用授权书本学位论文作者完全了解学校有关保留、使用学位论文的规定，同意学校保留并向国家有关部门或机构送交论文的复印件和电子版，允许论文

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5、担。学位论文作者签名：日期： 年 月 日6新脂肪细胞因子视黄醇结合蛋白4与肥胖及脂代谢的关系及机制研究摘 要第一部分 肥胖及2型糖尿病患者血清视黄醇结合蛋白4水平的临床研究目的：Yang 等利用基因芯片比较了脂肪组织特异性过表达葡萄糖转运子4（GluT4-Tg）和脂肪特异性剔除GluT4（ GluT4（-/-）小鼠附睾脂肪组织的基因表达谱，鉴定出一种新的参与胰岛素抵抗发生的脂肪细胞因子视黄醇结合蛋白4 (RBP4。然而，RBP4是主要由肝脏合成和分泌，但血清RBP4与肝脏的关系仍具争议。RBP4在人群中的研究资料尚少，它在人体内的病理生理意义仍需进一步的研究。本研究主要通过临床研究探讨：1.

6、血清RBP4在肥胖和2型糖尿病患者中的变化。2. 血清RBP4与体脂、糖、脂代谢及肝功能的关系。3. 血清RBP4与游离脂肪酸以及脂肪细胞因子，如脂联素之间的关系。 对象与方法：我们入选131例上海地区中国人，年龄2069岁，分组：正常对照组（NC）（n=31）和正常糖耐量超重/肥胖者（OW/OB-NGT）（n=31）、2型糖尿病正常体重组（NW-T2DM）（n=33）和2型糖尿病伴超重/肥胖组（OW/OB-T2DM）（n=36）。采用HOMA-IR评价各组胰岛素抵抗程度，测定受试者的体重指数（BMI）、腰臀比（WHR），体脂含量（Fat%）；检测空腹状态下血糖（FPG）、糖化血红蛋白（HbA

7、1c）、谷丙转氨酶（ALT）、谷氨酰转肽酶（GT）、胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、游离脂肪酸（FFA）、胰岛素（FINS）、脂联素（ADP）和RBP4。结果：71. 校正年龄后，男性的血清RBP4显著高于女性 (30.00±0.78 vs . 27.27±0.80g/ml，P 0.05。校正年龄、性别后，OW/OB-NGT 及OW/OB-T2DM组的血清RBP4水平显著高于NW-NGT组 (29.85±6.60，30.86±6.11 g/ml vs . 25.47±6.84

8、 g/ml，均P 0.05。2. NW-T2DM与NW-NGT组间的血清RBP4差异无显著性(25.47±6.84 vs 28.35±5.42 g/ml，但显著低于OW/OB-T2DM (30.86±6.11 vs . 28.35±5.42 g/ml， P 0.05。3. 单因素回归分析见到，血清RBP4与BMI、Fat%、W、WHR、TG及HOMA-IR呈显著正相关，未见到RBP4与ALT和GT有显著相关。多元逐步回归分析见到，WHR，TG和年龄是血清RBP4的独立相关因素。4. 将131名研究对象再次分组：正常甘油三酯伴正常腰臀比组（NTG-NCO）

9、TG1.7mmol/L，WHR0.90（男性），WHR0.85（女性）（n=39），正常甘油三酯伴中心性肥胖组（NTG-NCO）（n=43），高甘油三酯伴正常腰臀比组（HTG-NCO）（n=11）和高甘油三酯伴中心性肥胖组（HTG-CO）（n=38）。校正年龄、性别后，HTG-NCO和HTG-CO两组的血清RBP4水平均显著高于NTG-NCO和NTG-CO组(28.89±0.87 vs. 26.20±0.97 g/ml；(31.59±0.97 vs . 27.39±1.58 g/ml，均P 0.01；HTG-CO的RBP4水平显著高于HTG-NCO组(3

10、1.59±0.97 vs . 28.89±0.87 g/ml， P 0.01，但在NTG-CO与NTG-NCO两组间的血清RBP4水平差异无显著性(27.39±1.58 vs . 26.20±0.97 g/ml，P >0.05。小结：1. 肥胖者的血清RBP4显著升高。2. 血清RBP4与WHR，TG，年龄呈正相关。3. RBP4与血糖、血压、血脂以及中心型肥胖等与胰岛素抵抗有关指标有着不同程度的相关，表明RBP4是提示代谢综合征的一项血清学标志物。4. 肥胖者和糖尿病患者的ALT 和GT较高，其肝脏可能存在不同程度脂质沉积，但我们未发现这组人群的

11、血清RBP4变化与ALT 和GT有显著相关。8第二部分 视黄醇结合蛋白4在大鼠各组织中的表达目的：RBP4在肝脏、肾、脂肪和骨骼肌等多种组织均有合成。本研究通过动物试验，阐明生理状态下RBP4在机体各组织的表达水平，为研究生理及病理状态下RBP4表达水平变化提供依据。材料与方法：应用RT-PCR 和免疫组化的方法，对5只健康雄性SD 大鼠的主要器官（肝脏、脂肪、骨骼肌、肾脏和心肌组织）RBP4的表达进行了测定及比较。结果：1. 根据PCR 产物测序结果，与Pudmed 上公布的各基因mRNA 标准序列进行比较分析，证实PCR 产物确为我们所需要的目标产物。2. RBP4在各组织表达强度分别为：

12、肝脏（3.52±0.39），肾脏（3.63±0.63），脂肪（0.64±0.11），肌肉（0.38±0.06）和心脏（0.24±0.10）。3. RBP4弥漫分布于肝细胞以及胆管内；充满肾小管管腔及其上皮组织；散在脂肪细胞周边以及骨骼肌和心肌细胞内。4. 健康雄性SD 大鼠脂肪组织中RBP4与GluT4mRNA 的表达水平呈负相关（相关系数r= -0.667，P=0.219），但未达统计学意义。小结：1. RBP4在肝脏、脂肪、骨骼肌、肾脏和心肌组织均有表达，以肝脏和肾脏表达最强，脂肪其次，肌肉和心脏最少。2. RBP4弥漫分布于肝细胞以及胆管

13、内；充满肾小管管腔及其上皮组织；散在脂肪细胞周边以及骨骼肌和心肌细胞内。3. 在健康雄性SD 大鼠脂肪组织中，未见到RBP4与GluT4的相关。9第三部分 非诺贝特对高脂、高糖喂养大鼠血清、肝脏及脂肪组织视黄醇结合蛋白4表达的影响目的：RBP4新功能的发现，为治疗胰岛素抵抗和糖尿病提供了新的靶点。贝特类药物具有减重和改善胰岛素敏感性的功能。动物实验证明改善胰岛素敏感性可降低体内 RPB4水平，故推测这类药也可能有降低体内RBP4水平的作用。本研究通过动物试验探讨：1. RBP4在高脂肥胖胰岛素抵抗大鼠模型血清、肝脏和脂肪组织中的变化。2. 非诺贝特对高脂肥胖胰岛素抵抗大鼠模型血清、肝脏和脂肪组

14、织中RBP4和GluT4水平的影响。材料与方法：40只雄性SD 大鼠随机分为5组，普通饮食（NC）组、高脂饮食对照（FC）组和高糖饮食对照（SC）组，高脂饮食治疗（FF）组和高糖饮食治疗（SF）组，每组8只大鼠。喂养6周后，NC组予生理盐水，FC和SC 组予牛奶，治疗组予非诺贝特100mg/kg灌胃2周后，行口服糖耐量试验和胰岛素耐量试验检测胰岛功能，取空腹血清检测血脂和胰岛素等，并取附睾、肾周脂肪和肝脏组织称重，计算脂体比和饲养效率，RT-PCR检测附睾脂肪和肝脏组织RBP4和GluT4 mRNA表达水平。结果：1. FC 和SC 组大鼠糖耐量和胰岛素耐量受损，血脂紊乱，空腹血糖和胰岛素升高

15、，脂体比增加，肝脏出现了脂质沉积。FC和SC 组的大鼠血清RBP4水平显著高于NC 组1.84和1.57倍，附睾脂肪组织RBP4mRNA 水平显著高于NC组2.47倍和2.35倍，而GluT4显著低于NC 组1.5倍和1.37倍，而三组肝脏RBP4mRNA 水平无显著差异。2. 非诺贝特治疗后，治疗组体重、脂体比和饲养效率有所下降，血脂谱、胰岛素敏感性和肝脏脂质沉积较对照组均有所改善。FF 组血清RBP4和附睾脂肪组织RBP4mRNA 水平较FC 组分别下降了20.7和56.4；SF组较SC 组10分别下降了24和52，治疗组附睾脂肪组织GluT4mRNA 水平较对照组均有升高，但各组肝脏RB

16、P4 mRNA水平无显著差异。3. 单因素相关分析见到，血清RBP4与脂肪组织RBP4mRNA 水平显著相关，且两者均与体脂相关参数，糖脂代谢以及胰岛素抵抗相关指标呈显著相关，而与脂肪组织GluT4mRNA 水平呈显著负相关，肝脏组织RBP4mRNA 与各项代谢指标以及脂肪组织GluT4mRNA 水平均无显著相关。小结：1 成功地制作了高脂、高糖诱导胰岛素抵抗大鼠模型。2 高脂或高糖的饮食结构都可导致肥胖的发生，并刺激脂肪组织RBP4的表达增加。 RBP4与血糖，血脂代谢，腹内脂肪重量以及胰岛素抵抗密切相关，提示RBP4可能是一个代谢综合征的生物学标志物。3 非诺贝特可以改善血脂，增强胰岛素敏

17、感性，减少脂肪RBP4的表达。4 胰岛素抵抗状态下，脂肪细胞可能是血清RBP4主要来源。然而，由于我们未检测肌肉，肾脏等组织RBP4的变化，故不能排除PPAR 激动剂对这些组织RBP4合成的影响以及其他组织对血清RBP4的贡献。结 论1. RBP4与血糖、血脂、血压以及中心型肥胖等与胰岛素抵抗有关指标有着不同程度的相关，提示RBP4可能是提示代谢综合征的一项血清学标志物。2. RBP4在大鼠肝脏和肾脏表达最强，脂肪次之，而骨骼肌和心肌RBP4的表达最少。3. 非诺贝特可以改善血脂，减少腹内脂肪含量，增强胰岛素敏感性，减少脂肪RBP4的表达。4. 在胰岛素抵抗状态下，脂肪组织可能是血清RBP4主

18、要来源。然而，由于我们未检测肌肉，肾脏等组织RBP4的变化，故不能排除PPAR 激动剂对这些组织RBP4合成的影响以及其他组织对血清RBP4的贡献。关键词 视黄醇结合蛋白4，葡萄糖转运子4，胰岛素抵抗，腹型肥胖，非诺贝特 11上海交通大学医学院2004级博士研究生学位论文THE STUDY ON THE MECHANISM AND RELATIONSHIP OF THE NEW ADIPOCYTOKINE, RETINOL BINDING PROTEIN 4,OBESITY, AND LIPID METABOLISMABSTRACTPart 1 The clinical study on ob

19、esity, type 2 diabetes, and serum retinol binding protein 4Objective:Yang et al performed DNA array on epididymal adipose tissue RNA from the adipose specific overexpression of Glucose transporter 4 mice and GluT4 (-/- mice, and identified a new protein associated with insulin resistanceretinol bind

20、ing protein (RBP4. However, RBP4 was mainly expressed and secreted by liver, and the relationship of serum RBP4 and liver was still controversial. In short, the human study on RBP4 was limited and its pathophysiological roles in human should be further explored. By the clinical research, this study

21、illuminated that:1. The change of serum RBP4 in obesity and type 2 diabetes2. The relationships of serum RBP4, body fat, glucose and lipid metabolism, andliver function.3. The relationships of serum RBP4, free fat acid and adipocytokines, such asadiponectin.Subjects and methods:131 enrolled subjects

22、, aged from 20 to 69, were divided into 4 groups: normal control (NC (n=31, normal glucose tolerance with overweight or obesity (OW/OB-NGR (n=31, type 2 diabetes mellitus with normal weight (NW-T2DM (n=33, and type 2 12diabetes mellitus with overweight or obesity (OW/OB-T2DM (n=36. We evaluated the

23、extent of insulin resistance by use of HOMA-IR index, and measured body mass index (BMI, waist-to-hip ratio (WHR and body fat percent (Fat%. We assayed plasma glucose (FPG, Glycated Hemoglobin A1c (HbA1c, alanine aminotransferase (ALT, -glutamyltransferase (GT, total cholesterol (TC, triglycerides (

24、TG, high density lipoprotein-cholesterol (HDL-C, low density lipoprotein-cholesterol (LDL-C, free fat acid (FFA, insulin (FINS, RBP4 and adiponectin (APN in fasting state. Results:1. After adjustment of age, men had higher serum RBP4 level than women(30.00±0.78 vs 27.27±0.80 g/ml, P0.05. A

25、fter age and sex adjusted, serum RBP4 levels in OW/OB-NGR and OW/OB- T2DM were significantly elevated compared to the NC group (29.85±6.60，30.86±6.11 g/ml vs. 25.47±6.84 g/ml, both P 0.05.2. There is no significant difference between NC and NW-T2DM (25.47±6.84vs28.35±5.42 g/

26、ml. The serum RBP4 level in OW/OB-T2DM is significantly higher than that of NW-T2DM (30.86±6.11 vs. 28.35±5.42 g/ml, P0.05.3. Simple correlation analyses showed that serum RBP4 was correlated with BMI,Fat%, W, WHR, TG and HOMA-IR, and had no significant correlation with ALT and GT. Multipl

27、e linear regression analyses reveal that WHR, TG and age were independent variables for RBP4.4. Total of 131 subjects were re-divided into 4 groups: normal TG with normal WHR(NTG-NCO group TG1.7mmol/L, WHR0.90 in male, WHR0.85 in female (n=39, normal TG with central obesity (NTG-NCO group (n=43, hig

28、h TG with normal WHR (HTG-NCO group (n=11, and high TG with central obesity (HTG-CO group (n=38. After age, sex adjusted, serum RBP4 levels in the high TG group were significantly higher than that of the non- or central obesity groups with normal TG (28.89±0.87 vs. 26.20±0.97 g/ml; (31.59&

29、#177;0.97 vs. 27.39±1.58 g/ml, both P0.01; serum RBP4 levels in HTG-CO group was higher than that in HTG-NCO group (31.59±0.97 vs. 28.89±0.87 g/ml, P0.01. However, there was no significant difference in the RBP4 levels between the groups of NTG-CO and NTG-NCO(27.39±1.58 vs. 26.20

30、±0.97 g/ml, P>0.05.Part 1 conclusion:1. Serum RBP4 was elevated in obesity.2. Serum RBP4 was positively correlated with WHR, TG and age.3. It demonstrated that RBP4 was related with the parameters about insulin resistance,such as lipid profiles and central obesity, and implied that RBP4 coul

31、d be a serum marker for identifying metabolic syndrome.4. The obesity and T2DM patients in our study had higher ALT and GT, whichinferred that there would be lipid accumulating in their livers to some extent, whereas we did not find the facts that RBP4 was associated with ALT and GT in these groups.

32、Part 2 The expression levels of retinol binding protein 4 in various tissues of rats Objective:RBP4 was produced in many tissues, such as liver, kidney, adipose, muscle and so on. This study explored the RBP4 levels in various tissues in the physiological state to provide the evidence on the change

33、of RBP4 levels in the pathophysiological states via animal experiments.Materials and methodsWe evaluated the RBP4 levels in the main organs (liver, adipose, muscle, kidney and myocardial tissues of 5 healthy male SD rats by RT-PCR and immunohistology. Results:1. According to the results of sequencin

34、g PCR products, and comparison betweeneach mRNA standard sequences on Pubmed and PCR products, we confirmed that PCR products were the objective products that we wanted.2. The expression levels of RBP4 in various tissues were liver (3.52±0.39, kidney(3.63±0.63, adipose (0.64±0.11, mus

35、cle (0.38±0.06 and myocardial tissue (0.24±0.10.3. RBP4 was diffused in hepatocytes and billiary ducts; accumulated in tubular andepithelial tissue of kidney; scattered on the board of adipocytes and in muscle and myocardial cells.4. RBP4 was negatively correlated with GluT4mRNA in adipose

36、 tissues of healthymale SD rats, but it had no significance.Part 2 conclusion1. RBP4 was expressed in liver, adipose, muscle, kidney and myocardial tissues, and itwas higher in the liver and kidney, moderate in the adipose, and lower in muscle and myocardial tissues.2. RBP4 was diffused in hepatocyt

37、es and billiary ducts; accumulated in tubular andepithelial tissue of kidney; scattered on the board of adipocytes and in muscle and myocardial cells.3. We did not find the relationship between RBP4 and GluT4 in the adipose of healthymale SD rats.Part 3 The influence of fenofibrates on the expressio

38、n of RBP4 in serum, liver and adipose of rats fed on high fat or high sugar dietsObjective:The discovery of the new function of RBP4 provided the treatment target on insulin resistance and diabetes. Fibrates had effects of losing weight and increasing insulin sensitivity. Animal experiments showed i

39、mprovement of insulin sensitivity could lowerthe serum level of RBP4, so we hypothesized that fribrates also could have this effect. Via animal experiments, this study discussed:1. The change of RBP4 in serum, liver and adipose of rats with hyperlipidemia andinsulin resistance.2. The influence of fe

40、nofibrates on the expression of RBP4 and GluT4 in serum, liverand adipose of rats with hyperlipidemia and insulin resistance.Materials and methods:40 Male SD rats were randomly divided into 5 groups, normal diet (NC group, high fat diet control (FC group, high sugar diet control (SC group, high fat

41、diet treated by fenofibrate (FF group, and high sugar diet treated by fenofibrate (SF group, and each group included 8 rats. After 6 weeks fed by different diets, NC group was gavaged by normal saline, FC and SC groups were gavaged by milk, and the treatment groups were gavaged by fenofibrate, 100mg

42、/kg for 2 weeks. Then we performed oral glucose tolerance test and insulin tolerance test to assay islet function, and collected the fasting serum to measure lipid profiles and insulin and so on. We also weighed epididymal adipose, adipose around kidney and liver, and calculated fat to body weight r

43、atio and feeding efficiency. We employed the method of RT-PCR to relatively quantify RBP4 and Glut4 mRNA levels in the epididymal adipose and liver.Results:1. Rats in FC and SC groups had impaired glucose and insulin tolerance, and lipiddisorders. They also had higher fasting glucose and insulin lev

44、els, larger fat to body weight ratio, and more fat accumulation in liver than those in NC group. Serum RBP4 levels in FC and SC groups were significantly 1.84 and 1.57 times higher than those in NC group, respectively. And RBP4 mRNA levels in the epididymal adipose of these two groups were also sign

45、ificantly 2.47 and 2.35 times higher than those in NC group, respectively. GlutT4 mRNA levels in the epididymal adipose of these two groups were significantly 1.5 and 1.37 times lower than those in NCgroup, respectively. However, the RBP4 mRNA levels in rat livers between these three groups had no s

46、ignificant difference.2. The weight, fat to body weight ratio and feed efficiency of rats treated byfenofibrate were decreased, and lipid profiles, insulin sensitivity and fat accumulation in the liver in these rats were also improved. Serum RBP4 and RBP4 mRNA levels in the epididymal adipose of rat

47、s in FF group were 20.7% and 56.7% lower than those in FC group; those of rats in SF group were 24% and 52% lower than those in SC group, and GluT4 mRNA levels in the epididymal adipose of the rats received the treatment also increased to some extent, but the RBP4 mRNA levels in rat livers between t

48、he treatment groups and model control groups had no significant difference.3. Simple correlation analyses showed serum RBP4 was associated with RBP4 mRNAlevels in the adipose，and these two factors were both significantly correlated with the parameters, which were related to body fat distribution, gl

49、ucose and lipid metabolism, and insulin resistance, and negatively correlated with GluT4 mRNA levels in the adipose, while RBP4 mRNA levels in the liver were not associated with anyone of those parameters or GluT4 mRNA levels in the adipose.Part 3 conclusion:1. The rat models with insulin resistance

50、 induced by high fat or high sugar diets weresuccessfully founded.2. High fat or high sugar diets could lead to obesity, and stimulate the expression ofRBP4 in the adipose. RBP4 was closely related with glucose and lipid metabolism, visceral fat mass and insulin resistance, which indicated that RBP4

51、 might be a biological marker for metabolic syndrome.3. Fenofibrate increased insulin sensitivity and attenuate RBP4 expression in theadipose by the improvement of lipid disorders and reduction of visceral fat contents.4. In insulin resistance state, adipocytes might be a main source for serum RBP4.

52、However, because we did not assay the RBP4 expressions in other tissues, such as muscle and kidney, we could not exclude the contribution of other tissues to serum RBP4 in the state of insulin resistance, and the influence of PPAR agonist on RBP4 expression in those tissues.Conclusion1. RBP4 was rel

53、ated with the parameters about insulin resistance, such as lipidprofiles and central obesity, and implied that RBP4 could be a serum marker for identifying metabolic syndrome.2. RBP4 was expressed in liver, adipose, muscle, kidney and myocardial tissues, and itwas higher in the liver and kidney, mod

54、erate in the adipose, and lower in muscle and myocardial tissues.3. Fenofibrate increased insulin sensitivity and attenuate RBP4 expression in theadipose by the improvement of lipid disorders and reduction of visceral fat contents.4. In insulin resistance state, adipocytes might be a main source for

55、 serum RBP4.However, because we did not assay the RBP4 expressions in other tissues, such as muscle and kidney, we could not exclude the contribution of other tissues to serum RBP4 in the state of insulin resistance, and the influence of PPAR agonist on RBP4 expression in those tissues.KEY WORDS Ret

56、inol binding protein 4, glucose transporter 4, insulin resistance, fenofibrate第一部分肥胖及2型糖尿病患者血清视黄醇结合蛋白4水平的临床研究引言肥胖者的脂肪细胞肥大及数量增多，可导致脂肪细胞分泌的细胞因子表达增强或减弱1, 2，如脂联素、抵抗素、瘦素、内脂素、肿瘤坏死因子（TNF-）、白介素6(IL-6、纤溶酶原激活物抑制剂-1（PAI-1）及血管紧张素原等，从不同层次影响胰岛素的效应，成为胰岛素抵抗形成的主要因素3-10。胰岛素抵抗可导致胰岛素代偿性的高分泌以补偿胰岛素作用的不足，从而维持血糖的正常，当胰岛素的分泌

57、不能满足糖调节需要时，即可出现高血糖 11。众多研究证实胰岛素抵抗不仅是糖尿病的病因之一，也是高血压、血脂异常及动脉粥样硬化的共同危险因素12, 13。血清视黄醇结合蛋白4（RBP4）基因位于10q23-24，mRNA 全长941bp ，其编码的蛋白质由201个氨基酸组成，主要由肝脏分泌，新近研究发现它也是由脂肪细胞分泌的一种蛋白质，参与肥胖与胰岛素抵抗(IR发生机制，但其在人体内确切的病理生理功能尚未完全阐明14, 15。胰岛素抵抗的患者往往存在低脂联素血症和高游离脂肪酸血症，它们与RBP4的关系也仍待深入研究16-18。本研究在糖耐量正常者和2型糖尿病者中测定血清游离脂肪酸、胰岛素、脂联素

58、和视黄醇结合蛋白4水平，并分析了RBP4等因子在各组人群间水平的变化，探讨它们与肥胖程度、胰岛素抵抗、及糖脂代谢之间的关系。对象与方法一、 对象:在前来本院进行常规体检以及内分泌科门诊就诊者中，选取131例上海地区中国人，男性67例，女性64例，年龄2069岁。按WHO(1999糖尿病诊断标准分：正常糖耐量（NGT ）组64例和2型糖尿病（T2DM ）组67例。进一步以WHO(1998肥胖诊断标准分组：正常糖耐量正常体重 (NW-NGT 组33例，正常糖耐量超重/肥胖 (OW/OB -NGT 组31例，正常体重2型糖尿病(NW- T2DM 组31例，超重/肥胖2型糖尿病 (OW/OB- T2DM 组36例。研究对象均接受75 g口服葡萄糖耐量试验(OGTT，本研究采用82.5g 葡萄糖粉（含1分子结晶水）。除外女性育龄患者如服用避孕药物者；肝、肾功能异常者；皮质醇增多症；无酮症酸中毒、冠心病、肾病等糖尿病严重并发症；合并高血压者服用降压药血压控制在140/90 mmHg；除外谷氨酸脱羧酶抗体（GAD ）和酪氨酸磷酸酶抗体（IA