【作者】 陈容平；

【导师】 蔡德鸿；

【作者基本信息】 南方医科大学 ， 内分泌与代谢病学， 2011， 硕士

【摘要】 [研究背景]非酒精性脂肪性肝病(NAFLD)是指除外酒精和其他明确的肝损害因素所致的、以弥漫性肝细胞大泡性脂肪变为主要特征的临床病理综合征,包括单纯性脂肪肝以及由其演变的非酒精性脂肪性肝炎(NASH)和肝硬化。随着生活水平的改善和生活方式的改变,肥胖症和糖尿病的发病率不断增加,2型糖尿病(T2DM)合并非酒精性脂肪性肝病者越来越常见,但其发生、发展的机理尚未完全明了,许多研究表明胰岛素抵抗(IR)可能是两者共同的发病环节之一。以往研究发现,脂肪器官分泌的多种脂肪因子通过自分泌、旁分泌、内分泌的途径参与体内各种代谢过程,在胰岛素抵抗发病机制中发挥重要的作用。Yang等利用基因芯片鉴定出一种新的脂肪因子一视黄醇结合蛋白4(RBP4)。在胰岛素抵抗状态下,RBP4的表达会明显高出正常水平。它能够通过血液循环影响骨骼肌和肝脏对葡萄糖的利用,被称为联系全身胰岛素抵抗的信号分子。越来越多的研究发现RBP4作为一种新的脂肪因子,参与了胰岛素抵抗和2型糖尿病的发生。同时,RBP4在NAFLD发病中的作用也日益受到关注,但目前尚未见RBP4与2型糖尿病合并非酒精性脂肪性肝病相关研究的报道。[目的]通过测定RBP4和FFA在不同代谢状态人群中的水平,并分析其与胰岛素抵抗和2型糖尿病合并非酒精性脂肪性肝病一般临床与实验室指标的相关性,为进一步研究RBP4及FFA在该病发病中的作用提供依据。[方法]选取2010年6月-2010年12月南方医科大学珠江医院住院病人及体检者109例。纳入标准：根据2006年中华医学会肝脏病学分会《非酒精性脂肪性肝病诊疗指南》的临床诊断标准分为A组：正常组(25例)、B组：2型糖尿病组(43例)和C组：2型糖尿病合并非酒精性脂肪性肝病组(41例)。对所有入组人群采集病史、进行体表测量及填写基线资料登记表,肝脏B超检查；测量身高(m)、体重(kg)、体重指数(BMI)、腰围(WC)、腰臀比(WHR)：空腹状态下采取肘静脉血,用ELISA法测定空腹血清视黄醇结合蛋白4(RBP4)及游离脂肪酸(FFA)水平,同时测定所有受试者的总胆固醇(TC)、甘油三脂(TG)、空腹血糖(FBG)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ谷氨酰转肽酶(GGT),空腹血清胰岛素(FINS),以稳态模型评估法计算胰岛素抵抗指数(HOMA-IR):HOMA-IR=FBG x FINS/22.5。应用SPSS 13.0统计学软件按照组别进行比较和相关分析。计量数据采用均数±标准差(x±s)表示,多组间比较用完全随机设计资料的单方向方差分析(One-way ANOVA),多重比较用LSD法；正态分布资料方差不齐者使用Dunnett T3法比较；偏态分布资料进行自然对数转换后进行比较,无法转为正态分布的偏态分布资料使用多个独立样本非参数检验(K Independent Samples Test);年龄比较采用卡方检验；相关分析采用Spearman相关分析；线性回归采用多元回归方程。P<0.05作为差异有统计学意义。[结果](1)血清视黄醇结合蛋白4含量在A组、B组、和C组逐渐升高(A：5.661±3.043；B12.701±7.145：C 18.954±8.459),各组间差异均有统计学意义(P<0.001)：(2)三组人群血清中游离脂肪酸水平：(A：0.121±0.067；B：0.262±0.216；C0.557±0.276),A最低,C组最高,差异均有统计学意义(P<0.05)。(3)反映胰岛素敏感性指标的胰岛素抵抗指数HOMA-IR在三组人群分别为3.33±3.60；5.80±3.55；9.07±10.53,C组高于其他两组,差异有统计学意义(p<0.05),而A和B组比较,差异无统计学意义。腰围和腰臀比中,C组高于B组,B组高于A组,差异有统计学意义。(4)Spearman相关分析发现视黄醇结合蛋白4水平与BMI呈正相关(r=0.216P<0.05),与WC、WHR呈正相关(r=0.355,0.367,P<0.05),与HOMA-IR呈正相关(r=0.327,P<0.001),与FFA呈正相关(r=0.538,P<0.001),与FPG呈正相关(r=0.416,P<0.001),与TC、TG呈正相关性(r=0.289、0.374,P<0.001)。RBP4与年龄及空腹胰岛素不相关(r=0.036、0.129,P>0.05)。[结论](1)2型糖尿病合并非酒精性脂肪性肝病患者的胰岛素抵抗程度明显均高于正常组和2型糖尿病不合并组,提示胰岛素抵抗可能在糖尿病非酒精性脂肪性肝病发病中起一定作用。(2)血清视黄醇结合蛋白4水平在2型糖尿病组和2型糖尿病合并非酒精性脂肪性肝病组明显升高,其含量与BMI、HOMA-IR、WC、WHR、FFA、FPG、TC、TG呈正相关,提示其与超重、胰素抵抗增加和NAFLD发病有关。(3)游离脂肪酸在2型糖尿病合并非酒精性脂肪性肝病组最高,其与RBP4呈线性正相关,提示FFA系该病的另一重要参与因素。更多还原

【Abstract】 [Background]NAFLD is a clinical pathologic syndrome mainly characterized by diffuse hepatic steatosis in the absence of alcohol and other clear factors of hepatic damages, including simple fatty liver, non-alcoholic steatohepatitis(NASH) and cirrhosis. With the improvement of living standards and lifestyle changes, obesity and the onset of diabetes, especially type 2 diabetes(T2DM) become increasingly common in NAFLD patients. But the mechanism of its occurrence and development are not yet fully-understood, many studies have shown that insulin resistance (IR)may be one of the common links in the incidence of both.Previous studies have found that the fat factors secreted by the fat organ participate in various metabolic processes in vivo through autocrine, paracrine and endocrine pathways,which plays and very significant role in the pathogenesis of insulin resistance. Yang and other researchers had identified a new factor-retinolbinding protein 4 (RBP4) by gene chip,. In the state of insulin resistance, RBP4 expression will be significantly higher than normal. It can affect the glucose utilization in the liver and the muscles through blood circulation,which is known as the whole body IR contact signaling molecule More and more studies have found that RBP4, as a new fat factor, is involved in insulin resistance and type 2 diabetes. At the same time,the RBP4 in the pathogenesis of NAFLD is also of great concern recently. But no research are reported of RBP4 in T2DM patients with NAFLD.[Objective]We measure the level of RBP4 and FFA in different groups and analyze the correlation between the clinical and laboratory indicators of IR and T2DM with NAFLD,which will also provide some evidences for the further research of RBP4 and FFA.[Methods]We chose 109 patients in Zhujiang Hospital of Southen Medical University from June.2010 to Nov.2010. We devided them according to "the Guideline of NAFLD"presented by Chinese Society of Hepatology,CMA in 2006 into 3 groups. Group A:normal control(25 cases), group B:T2DM(43 cases), group C:T2DM with NAFLD(41 cases). We collected the history of the patients,finished the baseline information, investigated the financial condition, did the liver ultrasound, measured the height,weight and BMI. We also take their fasting blood to test the RBP4 and FFA level by E1ISA sandwich technique together with TC,TG,FBG,ALT,AST,GGT,FINS and the HOMA-IR (HOMA-IR=FBG x FINS/22.5).SPSS 13.0 is used to do the analysis.[Results]1.RPB4 rised gradually in group A,Band C(A:5.661±3.043;B 12.701±7.145;C 18.954±8.459),the difference between every group has statistical significance.2.The FFA level:(A:0.121±0.067;B:0.262±0.216;C 0.557±0.276), the difference also has statistical significance.3. HOMA-IR:3.33±3.60; 5.80±3.55; 9.07±10.53.the Data in Group C is lower than the other groups, difference has statistical significance, but comparing A with B,there is no statistical significance. Waist circumference and waist-hip ratio, C group than in B group, B group than in A group, the difference was statistically significant.4.According to the Spearman Correlation Analysis:RBP4 is positively correlated with BMI,HOMA-IR,WC,WHR,FFA,TC,TG and FPG,but is not related to age and FINS.Conclusion1.The IR grades are higher in T2DM patients with or without NAFLD,which shows that IR is a pathogenic factor of T2DM and NAFLD.2. The RBP4 level goes obviously higher in T2DM patients with or without NAFLD, and is positively correlated with BMI,HOMA-IR, WC,WHR,FFA, FPG,TC, and TG level, which clues to the onset of Overweight,IR and NAFLD.3. Free fatty acids in type 2 diabetic patients with nonalcoholic fatty liver disease was the highest of all, and is linear correlated with RBP4, suggesting that FFA is another important factor in this disease.更多还原