【作者】 杨帆；

【导师】 孙健平；

【作者基本信息】 青岛大学 ， 公共卫生（专业学位）， 2020， 硕士

【摘要】 研究背景与目的:肥胖与2型糖尿病(T2DM)均为长期代谢紊乱性疾病,其受遗传、环境、社会、经济、文化、生活方式等多方面因素影响,已成为影响全球居民健康的重要公共卫生问题。体质指数(BMI)、腰围(WC)、腰臀比(WHR)及腰高比(WHtR)是较常见的反映人体肥胖水平的指标,虽目前已有关于肥胖指标与T2DM关联的研究,但研究结果并不一致。因此,本研究拟分析不同肥胖指标(BMI、WC、WHR、WHtR)与新诊T2DM患病的关联,并进一步探讨其能否作为筛查新诊T2DM患病的简单工具,同时采用生物信息学方法来探讨肥胖、腹型肥胖与T2DM关联的内在分子生物学机制,为肥胖和T2DM的预防与治疗提供更精准的理论基础。方法:1.采用横断面研究分析不同肥胖指标与新诊T2DM的关联。于2006年和2009年在青岛12区市中采用四阶段分层随机抽样的方法抽取在该地区居住5年以上、年龄35～74岁的常住居民12 100例,实际调查到10 465例,排除已诊T2DM患者及BMI、WC、WHR、WHtR、空腹血浆血糖(FPG)、2小时血浆血糖(2h PG)信息缺失的研究对象,最终纳入横断面研究的研究对象共7 671例。采用Pearson相关及多元线性回归分析不同肥胖指标(BMI、WC、WHR、WHtR)水平与FPG、2h PG水平的相关性,采用Logistic回归分析其对新诊T2DM患病的影响,进一步采用受试者工作特征曲线(ROC曲线)来分析不同肥胖指标筛查新诊T2DM患病的效果。2.采用生物信息学分析来探讨肥胖、腹型肥胖与T2DM关联的内在分子生物学机制。借助GEO Datasets数据库来挖掘肥胖、腹型肥胖与T2DM相关的基因,并筛选出肥胖与T2DM、腹型肥胖与T2DM共同的差异表达基因(DEGs),将DEGs通过DAVID在线软件进行基因本体论(GO分析)和KEGG通路等方面的富集分析。结果:1.横断面研究分析结果显示,随着BMI、WC、WHR、WHtR水平的升高新诊T2DM的患病率在总人群和男性中呈上升趋势(P<0.001),但在女性中,以BMI水平划分的低体重组新诊T2DM患病率高于正常组(P<0.001)。Pearson相关分析、多元线性回归分析均显示,在总人群、男性和女性中BMI、WC、WHR、WHtR与FPG、2h PG均成正相关(P<0.001)。调整了相关混杂因素后,多元Logistic回归结果显示,在总人群和女性人群中超重组、肥胖组、分别依据WC、WHR和WHtR划分的腹型肥胖组较正常组新诊T2DM患病风险均升高,总人群中OR及95%CI分别为1.35(1.12,1.62)、2.05(1.67,2.51)、1.59(1.35,1.87)、1.42(1.22,1.65)、1.49(1.26,1.75);女性中OR及95%CI分别为1.48(1.14,1.93)、2.13(1.61,2.81)、1.61(1.27,2.03)、1.59(1.28,1.97)和1.66(1.30,2.13)。而在男性中,仅以BMI水平划分的肥胖组、以WC水平划分的腹型肥胖组新诊T2DM患病风险高于正常组,OR及95%CI分别为1.86(1.38,2.53)和1.47(1.17,1.85);而以WHR和WHtR水平划分的腹型肥胖组与新诊T2DM患病无统计学意义(P>0.05)。总人群中,BMI、WC、WHR和WHtR筛查新诊T2DM的最佳切点分别是>25.57 kg/m~2、>84.30 cm、>0.84和>0.52,男性分别为>25.73 kg/m~2、>84.80 cm、>0.91和>0.52;女性分别为>25.55 kg/m~2、>85.80 cm、>0.84和>0.52。在总人群、男性和女性中,筛查新诊T2DM患病的最优肥胖指标均为WHtR(P<0.05),且最佳切点均为>0.52。2.GEO数据库分析显示,肥胖与T2DM关联的DEGs有150个,腹型肥胖与T2DM关联的有146个。GO分析表明肥胖、腹型肥胖与T2DM的共同DEGs主要参与了细胞外泌体、粘着斑等细胞组分,参与了蛋白质结合、肌动蛋白结合等分子功能。KEGG信号通路富集结果表明,肥胖与T2DM及腹型肥胖与T2DM的共同DEGs参与了Rap1信号通路和心肌细胞的肾上腺素信号传导。结论:1.在总人群、男性及女性中,BMI、WC、WHR、WHtR均与FPG、2h PG呈正相关;在总人群和女性中BMI、WC、WHR和WHtR水平的升高增加新诊T2DM患病风险,而在男性中WHR和WHtR的水平却与新诊T2DM患病风险无关;肥胖指标筛查新诊T2DM患病的效果不佳。2.肥胖、腹型肥胖可能通过细胞外泌体和黏着斑等细胞组分、蛋白质结合和肌动蛋白结合等分子功能与T2DM相关联,肥胖可能通过Rap1信号通路和心肌细胞的肾上腺素信号传导与T2DM相关联,但其可能的分子生物学机制需通过动物实验和/或细胞实验进一步深入探讨。更多还原

【Abstract】 Background and Objectives:Obesity and type 2 diabetes mellitus(T2DM)are long term disorder of metabolism,affected by genetic,environmental,social,economic,cultural and lifestyle factors.They have become important public health problem affecting the health of global residents.Body mass index(BMI),waist circumference(WC),waist to hip ratio(WHR)and waist to height ratio(WHtR)are common indicators reflecting the level of obesity,although there have been some studies on the association between obesity indictors and newly diagnosed T2DM,the results are inconsistent.Therefore,this study intends to investigate the association between different obesity indictors and risk of T2DM prevalence,and further explore whether different obesity indictors can be used as a simple tool for screening of the newly diagnosed T2DM,and discuss the internal molecular biology mechanism of obesity and T2DM.It provides a more accurate theoretical basis for the prevention and treatment of obesity and T2DM.Methods:A cross-sectional study was used to analysis the association between different obesity indictors and newly diagnosed T2DM.A four-stage random sampling method was used to recruit a general population representative of 12 100 citizens lived more than 5years and aged 35～74 years in 7 districts and 5 cities of Qingdao.A total of 10 465individuals were initially enrolled in this study.In this study,we had used strict exclusion criteria:diagnosed T2DM,and no data of BMI,WC,WHR,WHtR,fasting plasma glucose(FPG)and 2 hours post-load plasma glucose(2h PG).A total of 7 671 individuals who met the strict exclusion criteria were included for the final analysis.Pearson correlation and multivariate linear regression analysis were used to analyze the correlation between BMI,WC,WHR,WHtR and FPG,2hPG.Multivariable logistic regression analysis was used to analyze the association between different obesity indictors and the prevalence of newly diagnosed T2DM.Then we used Receiver operating characteristic curve(ROC curve)to analyze different obesity indictors screening of newly diagnosed T2DM prevalence.We used bioinformatics study to investigate the internal molecular mechanism of obesity,abdominal obesity and T2DM.With the help of GEO Datasets,we obtained the genes related to T2DM,obesity and abdominal obesity,and analyze the differentially expressed genes(DEGs).Finally,we perform gene function enrichment analysis with gene ontology(GO)and KEGG pathway on DEGs of obesity,abdominal obesity and T2DM by DAVID online software.Results:The cross-sectional study showed that the prevalence of newly diagnosed T2DM was on the rise with the increase of BMI,WC,WHR and WHtR in the general and men population,(P<0.001).However,the prevalence of newly diagnosed T2DM in low body weight group was higher than that in normal group in women population(P<0.001).Pearson correlation analysis and Multivariate linear regression analysis illustrated that BMI,WC,WHR and WHtR levels were positively correlated with FPG and 2h PG(P<0.001).When adjusted related confounding factors.Multivariate logistic regression analysis showed that the risk of newly diagnosed T2DM was higher in the overweight group,obesity group,and abdominal obesity group according to WC,WHR and WHtR than that in the normal group in the general and women population.The odds ratio(OR)and 95%confidence intervals(CI)were 1.35(1.12,1.62),2.05(1.67,2.51),1.59(1.35,1.87),1.42(1.22,1.65),1.49(1.26,1.75)in the general and 1.48(1.14,1.93),2.13(1.61,2.81),1.61(1.27,2.03),1.59(1.28,1.97),1.66(1.30,2.13)in women population,respectively.The risk of newly diagnosed T2DM in the obesity group and in the abdominal obesity according to WC was higher than that in the normal group,OR and 95%CI were 1.86(1.38,2.53)and 1.47(1.17,1.85),respectively,while the risk of newly diagnosed T2DM in the abdominal obesity according to WHR and WHtR was not statistically significant higher than that in the normal group in men population(P>0.05).The optimal cut-of values for screening of newly diagnosed T2DM were The optimal cut-of values for screening of newly diagnosed T2DM were BMI>25.57 kg/m~2,WC>84.30 cm,WHR>0.84and WHtR>0.52,respectively,in the general.BMI>25.73 kg/m~2,WC>84.80 cm,WHR>0.91 and WHtR>0.52,respectively,in the men population.BMI>25.55 kg/m~2,WC>85.80 cm,WHR>0.84 and WHtR>0.52,respectively,in the women population.The optimal obesity index for screening newly diagnosed T2DM was WHtR(P<0.05),and the optimal cut-of values was WHtR>0.52.According to GEO database analysis,there are 150 DEGs associated with T2DM and obesity,146 DEGs associated with T2DM and abdominal obesity.Go analysis showed that the common DEGs of obesity,abdominal obesity and T2DM were mainly involved in extracellular exosomes,focal adhesion,protein binding,actin binding and other cell components or molecular functions.Conclusions:The prevalence of newly diagnosed T2DM increased with the levels of BMI,WC,WHR and WHtR and they were positively correlated with blood glucose level.The risk of newly diagnosed T2DM increased with the levels of BMI,WC,WHR and WHtR in the general and women population.However,low accuracy for screening newly diagnosed T2DM were found in all indicators of obesity in both genders.Obesity and abdominal obesity may be related to T2DM through cell components such as extracellular exosomes,focal adhesion and molecular functions such as protein binding and actin binding.更多还原