肥胖相关性胰岛素抵抗研究：从流行病学到基因组学

发布时间：2018-06-04 15:19

本文选题：肥胖 + 胰岛素抵抗　；参考：《吉林大学》2015年博士论文

【摘要】：研究背景：肥胖在全球呈蔓延趋势，是慢性非传染性疾病的重要危险因素，威胁人类的身心健康和生命。本地区肥胖和超重流行特点及危险因素等流行病学资料并不完善，对肥胖相关性胰岛素抵抗与糖脂代谢紊乱认识不足；另外，如何选择有效的早期筛查肥胖和胰岛素抵抗的简便方法尚有争议。胰岛素抵抗是多种肥胖相关性疾病的共同病理生理基础，然而其发生的分子机制尚不完全明确。研究目的：明确本地区肥胖流行现状及其相关危险因素；了解肥胖与糖脂代谢紊乱、心血管疾病等疾病的相关性和发生风险；分析肥胖与胰岛素抵抗的相关性；评价不同体脂测量指标筛查肥胖及其相关疾病的价值；明确本地区中老年人近年来糖尿病发病率及其相关危险因素；评价不同胰岛素抵抗指标预测糖尿病发生的价值；通过基因组学的研究方法筛选脂肪组织胰岛素抵抗的差异表达基因，进而探讨脂肪组织胰岛素抵抗发生的可能机制及胰岛素抵抗发生过程中糖脂代谢紊乱特点。方法：第一部分为横断面调查研究，随机抽取长春市10080名40岁以上成人，进行问卷调查、体格检查和实验室检查，且每位调查对象均要进行口服葡萄糖耐量试验；借助Epidata和Office软件对数据进行整理，通过PASW统计软件进行数据分析；计算肥胖和超重患病率，进行肥胖危险因素的Logistic多元回归分析，计算肥胖体质指标与糖脂代谢指标的偏相关系数r，绘制各个体质指标筛查ROC曲线，计算ROC曲线下面积；第二部分为前瞻性队列研究，从第一部分非糖尿病患者中随机抽取2500人进行随访，计算糖尿病发病率，绘制不同胰岛素抵抗指标预测糖尿病发生的ROC曲线，计算ROC曲线下面积；第三部分为基因组学研究，从Gene Expression Omnibus（GEO）数据库中下载芯片数据，利用frozen robust multiarray analysis（fRMA）算法进行数据背景校正、标准化和汇总，通过芯片数据显著性分析（SAM）方法筛选出胰岛素抵抗与胰岛素敏感组的差异表达基因，假阳性错误率（FDR）控制在0.05水平，在Genecards数据库中确定差异表达基因的生物学意义，继而探讨胰岛素抵抗发生的可能分子机制。在各部分研究中，假设检验显著性标准α均取0.05，p0.05表示差异有统计学意义。结果：第一部分横断面研究实际完成调查9571人，超重者占43.20%，肥胖者占18.83%；男性超重和肥胖人群发生胰岛素抵抗分别占40.9%和64.9%；女性超重和肥胖人群发生胰岛素抵抗分别占49.4%和73.2%；男性和女性BMI与HOMA-IR的偏相关系数r分别为0.378和0.313；男性BMI筛查胰岛素抵抗的ROC曲线下面积为0.752，女性BMI筛查胰岛素抵抗的ROC曲线下面积为0.725。第二部分实际完成随访2297人，共随访6730人年，共发生糖尿病191例，糖尿病发病率为2.83人/百人年；胰岛素抵抗者发生糖尿病的风险约为非胰岛素抵抗者的2.2倍，超重和肥胖人群约是正常体重人群的1.7和2.3倍，血清甘油三酯边缘升高和高甘油三酯血症人群约是正常甘油三酯血症人群的1.2和2.0倍，血清高密度脂蛋白胆固醇降低人群约是非高密度脂蛋白胆固醇降低人群的1.7倍；HOMA-IR，TG/HDL-C，BMI和空腹胰岛素预测糖尿病发生的ROC曲线下面积分别为0.616，0.602，0.599，和0.576。第三部分共纳入2项研究，共49例基因芯片数据标本，筛选出差异表达基因386个，上调表达330个，差异较显著的有IL1RN，PLA2G7和MMP9，，与慢性炎症反应密切相关；下调表达56个，差异较显著的有SLC27A2，AGPAT9和ACACB，与脂肪合成密切相关。结论：长春市中老年人群是肥胖和超重的高发人群；胰岛素抵抗与肥胖关系密切。BMI是中老年男性人群筛查肥胖的最佳指标，而腰围和腰围身高比则是中老年女性的最佳筛查指标。长春市40岁以上成人糖尿病发病率高于其他地区研究结果；但糖尿病前期人群糖尿病发病率较低于其他地区研究结果。BMI可作为胰岛素抵抗的初筛指标，而TG/HDL-C可以作为联合HOMA-IR来评价肥胖人群的胰岛素抵抗程度并预测2型糖尿病的发生风险的另一指标。脂肪组织胰岛素抵抗发生与脂肪细胞炎症反应有关，炎症细胞浸润及炎症因子释放增加抑制脂肪细胞内胰岛素信号通路。脂肪组织胰岛素抵抗发生时，脂肪代谢紊乱是最主要的代谢异常表现，脂肪细胞内参与脂肪合成的相关酶系基因表达下调，抑制脂肪合成。
[Abstract]:Background : The prevalence of obesity in the world is an important risk factor for chronic non - communicable diseases , threatening the physical and mental health and life of human beings . Epidemiological data such as obesity and overweight in the region and risk factors are not perfect , and there is insufficient understanding of obesity - related insulin resistance and glycolipid metabolism disorder .
In addition , it is controversial how to select a simple and effective method for early screening of obesity and insulin resistance . Insulin resistance is a common pathological basis for multiple obesity - related diseases , but its molecular mechanism is not entirely clear .

Objective : To clarify the present situation of obesity epidemic in the region and its associated risk factors .
To understand the correlation and risk of obesity and glycolipid metabolism disorders , cardiovascular diseases and other diseases ;
To analyze the correlation between obesity and insulin resistance ;
To evaluate the value of different body fat measurement indexes in screening obesity and related diseases ;
The incidence of diabetes mellitus and its associated risk factors in middle - aged and elderly people in the region were identified .
To evaluate the value of different insulin resistance indices in predicting the onset of diabetes ;
The differential expression of insulin resistance in adipose tissue was screened by genomics , and the possible mechanism of insulin resistance in adipose tissue and the characteristics of glycolipid metabolism in insulin resistance were discussed .

Methods : The first part was divided into the cross - sectional survey , and 100 80 adults over 40 years of age were randomly selected to carry out questionnaire , physical examination and laboratory examination , and the oral glucose tolerance test was carried out in each survey subject ;
The data is collated with Epidata and Office software , and the data is analyzed by PASW statistical software ;
To calculate the prevalence of obesity and overweight , Logistic regression analysis of risk factors of obesity was carried out to calculate the correlation coefficient between obesity constitution index and glycolipid metabolism index ( r ) , and the ROC curve of each physical fitness index was drawn , and the area under ROC curve was calculated ;
The second part is prospective cohort study , and 2500 people are randomly selected from the first part of non - diabetic patients for follow - up , the incidence of diabetes is calculated , different insulin resistance indexes are drawn to predict the ROC curve of diabetes , and the area under ROC curve is calculated ;
In the third part , the data was downloaded from the GeneExpression Omnibus ( GEO ) database , and the data background correction , standardization and summarization were carried out by using the frozen robust multiarray analysis ( fRMA ) algorithm . The differential expression gene of insulin resistance and insulin sensitive group was screened by means of a chip data significance analysis ( SAM ) method .

Results : The first part of cross - sectional study actually completed the investigation of 9571 , overweight accounted for 43.20 % , and obesity accounted for 18.83 % ;
Insulin resistance in overweight and obese men accounted for 40.9 % and 64.9 % , respectively .
Insulin resistance in overweight and obese women accounted for 49.4 % and 73.2 % , respectively .
The correlation coefficient r between BMI of male and female was 0.378 and 0.313 , respectively .
The area of ROC curve for BMI screening insulin resistance was 0.752 , and the area under ROC curve of BMI screening insulin resistance was 0.725 . 2297 patients were followed up for 6730 years .
The risk of insulin resistance was 2.2 times that of non - insulin resistance , overweight and obese people were 1.7 and 2.3 times that of normal body weight group , serum triglyceride edge and high triglyceride were 1.2 and 2.0 times that of normal triglyceride group , and that of high density lipoprotein cholesterol in serum was 1.7 times lower than that of non - high density lipoprotein cholesterol .
The ROC curves under ROC curves were 0.616 , 0.602 , 0.599 and 0.576 , respectively .
The expression of SLC27A2 , AGPAT9 and ACACB was significantly correlated with fat synthesis .

Conclusion : The middle - aged and old people in Changchun are obese and overweight .
Insulin resistance is closely related to obesity . BMI is the best index for middle - aged and old men to screen obesity , while waist and waist height ratio is the best screening index for middle - aged and old women . The incidence of diabetes in adults over 40 years of Changchun is higher than that of other regions .
In the early stage of diabetes , the incidence of diabetes is lower than that in other regions . BMI can be used as the primary screening index of insulin resistance , and TG / HDL - C can be used as a combination of the insulin resistance of obese people and predict the risk of insulin resistance in type 2 diabetes mellitus . The fatty tissue insulin resistance is associated with inflammatory response of fat cells , inflammatory cell infiltration and inflammatory factor release increase the insulin signaling pathway in fat cells . In the event of insulin resistance , the lipid metabolism disorder is the most important metabolic abnormality , and the expression of related enzymes involved in fat synthesis is down regulated in fat cells , and fat synthesis is inhibited .
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R589.2

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