线粒体及其调控基因在糖脂异常发生机制中的作用
发布时间：2018-08-27 16:51
【摘要】：目的线粒体基因突变与线粒体DNA拷贝量减少共同参与线粒体功能障碍的发生,线粒体DNA拷贝量减少在年龄相关退行性疾病-2型糖尿病发病中起到重要的驱动性作用。本研究将从线粒体单基因突变的线粒体糖尿病家系入手,结合2型糖尿病的发病进程,探讨线粒体功能障碍与糖脂代谢异常的关系。通过建立线粒体内膜调控氧化磷酸化解偶联作用的解偶联蛋白2 (Uncoupling Protein 2, UCP2)基因敲除小鼠高脂饲养模型,探索UCP2及其上游调控基因在糖脂代谢中的作用,并在血糖谱连续的人群中(健康人群-糖尿病前期-2型糖尿病)分析UCP2及其上游调控基因氧化物酶体增殖物激活受体y (Peroxisome Proliferator Activated Receptor y, PPAR y)基因多态性特点。探寻饮食结构对线粒体功能及对位于染色体末端生物学老化的标志物-端粒长度(Telomere Length, TL)的影响,分析饮食在线粒体介导糖脂代谢异常中的作用,从遗传、环境因素两方面探讨2型糖尿病的发病机制。同时,探讨血脂比(TG/HDL-C)能否作为评估胰岛素抵抗以及胰岛β细胞分泌功能受损的临床指标,寻找预测2型糖尿病胰岛素抵抗、胰岛β细胞功能的简易标志物。方法人群研究对象：①线粒体糖尿病患者来自2007年4月至2015年12月间在北京协和医院内分泌科就诊的线粒体DNA 3243 AG位点突变的线粒体糖尿病患者16例；②血糖谱连续人群来自2014年3月至2015年1月间北京农村社区2型糖尿病管理模式的建立项目共599人；③队列研究基线人群来自2005年4月-2006年4月就诊于北京协和医院门诊的76例2型糖尿病患者。收集一般人口学特征、临床、生化资料、饮食结构问卷。线粒体DNA 3243位点基因突变检测采用直接测序法(Sanger法),突变位点碱基G／A峰值比定义为=碱基G峰值高度÷碱基A峰值高度。外周血线粒体DNA拷贝量、端粒长度的测定采用荧光实时定量多聚酶式反应。基因多态性分析采用质谱检测平台,检测8个UCP2功能区多态性位点(rs660339、rs659366.rs649446、rs586773、rs34408426、rs7109266、 rs3019463、rs591758),7个PPARγ功能区多态性位点(rs3856806,rs2920502,rs1702900、 rs73021485、 rs73813168、 rs2920503、 rs79310821)。氧化应激指标(SOD、 GR.8-oxo-dG)、炎症因子(IL-6、 TNF-a)测定采用酶联免疫吸附法测定。动物研究：C57BL/6背景的雄性UCP2-/-小鼠和同周龄C57BL/6背景的UCP2+/+小鼠。高脂饲养16周。肝脏组织基因表达谱采用全基因组表达芯片分析(Affymetrix Mouse Gene ST 1.0 array) 。结果1.线粒体DNA 3243 AG突变糖尿病患者临床特点及突变异质性与疾病谱间的关系16例线粒体糖尿病患者(起病年龄：35.0±14.6岁)伴明确的母系遗传家族史、体型偏瘦(BMI：19.5±2.36 kg/m2)、耳聋累及高频域。线粒体DNA 3243位点AG突变G/A峰值比与发病年龄呈显著负相关(相关系数r=-0.841,P0.001)。2.外周血线粒体DNA拷贝量与葡萄糖刺激后胰岛β细胞分泌功能的关联分析外周血线粒体DNA拷贝量与口服葡萄糖耐量后早相、总体胰岛素分泌指数呈显著性正相关,与30min、 60min、120min血糖呈显著性负相关,与空腹胰岛素分泌指数、血糖、血脂并不存在显著性相关。多元线性回归分析表明,外周血线粒体DNA拷贝量减少可增加葡萄糖刺激后8细胞功能受损风险(DI30:β=0.104, P= 0.019; DI120:P=0.116, P= 0.009)。多元logistic回归分析表明外周血线粒体DNA拷贝量与2型糖尿病发生风险呈显著性负相关(OR:0.468,95% CI:0.245-0.893, P=0.021).3.UCP2在糖腊代谢中的作用及其代谢通路分析持续高脂饲养状态下,UCP2-/-小鼠胰岛β细胞功能和胰岛素敏感性好于UCP2+/+小鼠,UCP2-/-小鼠血清总胆固醇、甘油三酯和游离脂肪酸显著性低于UCP2+/+小鼠。根据肝脏基因芯片分析,UCP2-/-组与UCP2+/+组间,"PPAR信号通路”中7种基因表达显著性上调,包括PPARγ,Acsl3,Lpl, Mel,Scdl,Fads2. PPAR另外两种异构体—PPARck PPAR8基因表达量在UCP2-/-组和UCP2+/+组间并不存在显著性差异。4.人群UCP2-PPARγ多态性与糖脂代谢异常相关性研究8个UCP2基因SNP位点等位基因、基因型在不同糖代谢状态人群间不存在显著性差异。PPARγ基因rs2920502位点等位基因碱基G、基因型GG时是糖代谢异常的保护因素(等位基因OR:0.818,95% CI:0.526-0.969,P=0.042;基因型OR:0.715,95% CI:0.527-0.97,P=0.031), GG基因型血脂TC、TG、LDL-C、 TG/HDL-C低于GC、CC基因。rs3856806位点等位基因碱基T、等位基因TT时是糖代谢异常的危险因素(等位基因OR:1.46,95%CI:1.055-2.017, P=0.022;基因型OR:1.58,95%CI:1.104-2.761,P=0.032).5.线粒体糖尿病与2型糖尿病、正常人群外周血DNA端粒长度比较端粒长度在线粒体糖尿病、2型糖尿病组显著性低于正常对照组,但线粒体糖尿病和2型糖尿病组间并不存在显著性差异(线粒体糖尿病vs 2型糖尿病vs正常对照：1.28±0.54 vs 1.14±0.43 vs 1.63±0.61,P=0.000)。外周血DNA端粒长度与线粒体DNA 3243突变位点碱基G/A峰值比并不存在显著性相关性(r=-0.156,P=0.646)。6.饮食成分、碳水化合物构成比对外周血DNA端粒长度及血糖的影响糖尿病组端粒长度较正常对照组显著性缩短(log(TL):血糖正常组vs糖尿病前期组vs糖尿病组：2.01±0.03 vs 1.97±0.03 vs 1.89±0.03,P=0.005)。端粒长度与每日饮食总能量摄入及饮食中脂类/碳水化合物比例不存在显著性相关,多元线性回归分析表明,豆制品、坚果、鱼类、海藻类是端粒长度的保护因素,甜饮料是其危险因素(豆类：β=0.105,P=0.018；坚果：p=0.110,P=0.011：鱼类:β=0.118,P=0.007：海藻类:β=0.116,P=0.009)。饮食中脂类、碳水化合物构成比和谷类、肉类与TNF-α呈显著性正相关(脂类：r=0.119,P=0.008；碳水化合物：r=0.094,P=0.043；谷类：r=0.091,P=0.048；肉类:r=0.405,P=0.009)。海藻类、奶制品摄入量与8-oxoˉdG呈显著性负相关(海藻类：r=-0.496,P=0.001；奶制品：r=-0.246,P=0.046),蔬菜、水果类摄入与GR呈显著性正相关(蔬菜：r=0.101,P=0.034；水果:r=0.125,P=0.045)。7.血脂比TG/HDL-C对胰岛素抵抗和胰岛β细胞功能的预测作用血糖谱连续的人群中,TG/HDL-C、TG可作为预测胰岛素抵抗的血脂标志(TG/HDL-C:ROC曲线下面积(AUROC):0.71,95% CI:0.66-0.75,P=0.000;TG:AUROC:0.71,95% CI:0.65-0.75,P=0.000);诊断胰岛素抵抗TG/HDL-C、TG最佳切点值分别为：1.11,1.33mmol/L。 TG/HDL-C与HOMA-β存在显著性负相关,ROC曲线下面积均小,不宜作为判断β细胞分泌受损的指标。2型糖尿病患者6年队列研究中,用DeltaC肽曲线下面积(Delta CP AUC)表示6年前后β细胞分泌功能的变化(Delta CP AUC=基线CP AUC-6年后CP AUC),根据Delta CP AUC二分位将受试者分为p细胞功能下降较慢组、下降较快组。β细胞功能下降较快组基线log (TG)/HDL-C值高于下降较慢组(0.103±0.033vs 0.083±0.030,P=0.027)。β细胞功能下降较快组基线空腹、标准餐后5个时点TG及曲线下面积均高于下降较慢组,TG与Delta CP AUC呈显著性正相关,且HDL-C低于下降较慢组,与Delta CP AUC呈显著性负相关。结论1.早发糖尿病患者伴母系遗传家族史、BMI正常或偏瘦、耳聋可强烈提示线粒体糖尿病的存在。外周血DNA直接测序法对线粒体DNA 3243位点AG突变进行鉴定,其突变G/A峰值比对线粒体疾病的起病年龄及疾病严重程度可起到简单的预测作用。2.在血糖谱连续的人群中,本研究首次发现,线粒体DNA拷贝量与葡萄糖刺激后的早相、总体胰岛素分泌功能呈显著性正相关,其对于餐后血糖的影响大于对空腹血糖的影响。3.UCP2缺乏通过PPAR信号通路提高胰岛素敏感性和β细胞功能来改善血糖、血脂,PPARγ多态位点(rs2920502、rs3856806)与糖脂代谢密切相关,是高脂饮食状态下调控UCP2表达的重要基因。4.端粒长度缩短可能参与糖尿病的发病机制,但并非线粒体糖尿病的特异性指标。饮食成分可能通过改变机体氧化应激和炎症状态影响端粒长度。5.在血糖谱连续的人群中,本研究首次发现,血脂比TG/HDL-C可作为胰岛素抵抗的预测标志。TG/HDL-C与空腹β细胞分泌功能存在显著性负相关。在2型糖尿病病程中,基线时Log (TG)/HDL-C值高预示胰岛β细胞功能障碍进展较快。
[Abstract]:Objective Mitochondrial gene mutation and mitochondrial DNA copy reduction are involved in the occurrence of mitochondrial dysfunction. Mitochondrial DNA copy reduction plays an important role in the pathogenesis of age-related degenerative disease-type 2 diabetes mellitus. To explore the relationship between mitochondrial dysfunction and abnormal glucose and lipid metabolism, a high-fat feeding model of uncoupling protein 2 (UCP2) knockout mice was established to investigate the role of UCP2 and its upstream regulatory genes in glucose and lipid metabolism and to explore the role of UCP2 and its upstream regulatory genes in blood lipid metabolism. Polymorphisms of UCP2 and its upstream regulatory gene, Peroxisome Proliferator Activated Receptor y (PPAR y), were analyzed in a population with continuous glucose profile (healthy subjects - pre-diabetes mellitus - type 2 diabetes mellitus). The effects of telomere length (TL) and diet on mitochondrial-mediated glucose and lipid metabolism were analyzed. The pathogenesis of type 2 diabetes mellitus was discussed from genetic and environmental factors. Methods A total of 16 patients with mitochondrial diabetes mellitus were selected from the Department of Endocrinology, Peking Union Medical College Hospital from April 2007 to December 2015, and 16 patients with mitochondrial DNA 3243 AG mutation were recruited. A cohort of 599 people from rural communities in Beijing from March 2014 to January 2015 were involved in the establishment of type 2 diabetes management model. Direct sequencing (Sanger method) was used to detect gene mutation at 3243 locus. The peak ratio of base G/A was defined as the peak height of base G and the peak height of base A. Seven polymorphic sites (rs3856806, rs2920502, rs1702900, rs73021485, rs73813168, rs2920503, rs79310821) in the PPAR gamma domain were identified. Oxidative stress indices (TND, GR.8-oxo-dG, IL-6, IL-a) were used for the determination of PPAR gamma domain polymorphism. Animal studies: male UCP2-/-mice with C57BL/6 background and UCP2+/+ mice with C57BL/6 background of the same age. High-fat feeding for 16 weeks. Gene expression profiles in liver tissues were analyzed by whole-genome expression microarray (Affymetrix Mouse Gene ST 1.0 array). Results 1. Clinical characteristics of diabetic patients with mitochondrial DNA 3243 AG mutation Relationship between point and mutation heterogeneity and disease spectrum in 16 patients with mitochondrial diabetes mellitus (onset age: 35.0 + 14.6 years old) with a clear maternal genetic family history, leanness (BMI: 19.5 + 2.36 kg / m2), deafness involvement and high frequency domain. The peak G/A ratio of mitochondrial DNA 3243 AG mutation was negatively correlated with onset age (correlation coefficient r = - 0.841, P 0.0). 01). 2. Correlation analysis of mitochondrial DNA copy in peripheral blood and secretory function of islet beta cells stimulated by glucose Multivariate linear regression analysis showed that the decrease of mitochondrial DNA copy in peripheral blood increased the risk of impaired 8 cell function after glucose stimulation (DI30: beta = 0.104, P = 0.019; DI120: P = 0.116, P = 0.009). Significant negative correlation (OR: 0.468, 95% CI: 0.245-0.893, P = 0.021). 3. The role of UCP2 in glucose and wax metabolism and its metabolic pathway analysis in UCP2 - / - mice islet beta cell function and insulin sensitivity were better than those in UCP2 + / + mice, and the serum total cholesterol, triglycerides and free fatty acids in UCP2 - / - mice were significantly lower than those in UCP2 + / free fatty acids. According to the liver microarray analysis, the expression of seven genes in the PPAR signaling pathway was significantly up-regulated between UCP2-/- and UCP2+/+ groups, including PPAR gamma, Acsl3, Lpl, Mel, Scdl, Fads2.PPAR, and the other two isoforms, PPARck PPAR8, were not significantly different between UCP2-/-and UCP2+/+ groups. Allele G of PPAR gamma gene rs2920502 was the protective factor for abnormal glucose metabolism (allele OR: 0.818, 95% CI: 0.526-0.969, P = 0.042; genotype OR: 0.042). 715,95% CI: 0.527-0.97, P = 0.031), GG genotype TC, TG, LDL-C, TG / HDL-C were lower than GC, CC gene. Allele T at locus. rs3856806 was a risk factor for abnormal glucose metabolism (allele OR: 1.46, 95% CI: 1.055-2.017, P = 0.022; genotype OR: 1.58, 95% CI: 1.104-2.761, P = 0.032). The length of telomere in peripheral blood was significantly lower in type 2 diabetes mellitus than in normal control group, but there was no significant difference between type 2 diabetes mellitus and mitochondrial diabetes mellitus (mitochondrial diabetes vs type 2 diabetes vs type 2 diabetes vs normal control: 1.28 + 0.54 vs 1.14 + 0.43 vs 1.63 + 0.61, P = 0.000). There was no significant correlation between the telomere length of peripheral blood DNA and the G/A peak ratio of mitochondrial DNA 3243 mutation site (r = - 0.156, P = 0.646). 6. Dietary composition, carbohydrate composition ratio of peripheral blood DNA telomere length and blood glucose were significantly shorter in diabetes mellitus group than in normal control group (log (TL): vs diabetes mellitus in normal blood glucose group. There was no significant correlation between telomere length and dietary total energy intake or lipid/carbohydrate ratio. Multivariate linear regression analysis showed that soybean products, nuts, fish and algae were protective factors for telomere length, and sweet beverage was a risk factor. Factors (legume: beta = 0.105, P = 0.105, P = 0.018; nut: P = 0.110, P = 0.011: fish: bet = 0.118, P = 0.011: fish: fish: fish: bet = 0.118, P = 0.007: algae: bet = 0.116, P = 0.009). Dielipid, carbohydrate composition ratio and cereal, meat and TNF-alphawere positively correl (lipid: r = 0.119, P = 0.008; carbohydrate: r = 0.094, P = 0.043; gluten: gluten: r = 0.043; gluten: r = 0.043; gluten: r = 0.041, r = 0.091, r = 0.09Meat Algae, dairy intake and 8-oxo-dG were negatively correlated (algae: r = - 0.496, P = 0.001; dairy products: r = - 0.246, P = 0.046). Vegetable and fruit intake were positively correlated with GR (vegetable: r = 0.101, P = 0.034; fruit: r = 0.125, P = 0.045). 7. TG/HDL-C and TG could be used to predict insulin resistance (AUROC: 0.71, 95% CI: 0.66-0.75, P = 0.000; TG: AUROC: 0.71, 95% CI: 0.65-0.75, P = 0.000); TG / HDL-C and TG best cut-off values were 1.11, 1.33 mmol/L. In a 6-year cohort study of type 2 diabetes mellitus, Delta CP AUC (Delta CP AUC = baseline CP AUC - 6 years later CP AUC) was used to represent the changes of beta cell secretory function before and after 6 years (Delta CP AUC = baseline CP AUC - 6 years later CP AUC) and the delta CP AUC binary was used to determine the impairment of beta cell secretion. The subjects were divided into two groups: the group with slower decline in P-cell function and the group with faster decline in beta-cell function. The baseline log (TG)/HDL-C values of the group with faster decline in beta-cell function were higher than those of the group with slower decline (0.103.033 vs 0.083.030, P = 0.027). The baseline fasting of the group with faster decline in beta-cell function was higher than that of the group with slower decline in TG and area under the curve at 5 time points after standard meal. Conclusion 1. Early onset diabetes mellitus patients with maternal genetic family history, normal or thin BMI, deafness can strongly suggest the existence of mitochondrial diabetes mellitus. Direct sequencing of peripheral blood DNA to identify mitochondrial DNA 3243 AG mutation, its mutation G / A Peak ratio can predict the onset age and severity of mitochondrial disease. 2. In the population with continuous blood glucose profile, this study found for the first time that mitochondrial DNA copy was positively correlated with the early phase after glucose stimulation, and the overall insulin secretion function was significantly positively correlated. The effect on postprandial blood glucose was greater than that on fasting blood. 3. UCP2 deficiency through PPAR signaling pathway to improve insulin sensitivity and beta cell function to improve blood glucose, blood lipids, PPAR gamma polymorphism sites (rs2920502, rs3856806) is closely related to glucose and lipid metabolism, is an important gene regulating UCP2 expression under high-fat diet. 4. Telomere length shortening may be involved in the pathogenesis of diabetes, but Dietary components may influence telomere length by altering oxidative stress and inflammation. 5. In a population with a continuous blood glucose profile, TG/HDL-C was found to be a predictor of insulin resistance for the first time. TG/HDL-C was negatively correlated with fasting beta cell secretion. During the course of type 2 diabetes, the high Log (TG) /HDL-C value at baseline indicated that the progression of islet beta cell dysfunction was faster.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R587.1
，
本文编号：2207865
[Abstract]:Objective Mitochondrial gene mutation and mitochondrial DNA copy reduction are involved in the occurrence of mitochondrial dysfunction. Mitochondrial DNA copy reduction plays an important role in the pathogenesis of age-related degenerative disease-type 2 diabetes mellitus. To explore the relationship between mitochondrial dysfunction and abnormal glucose and lipid metabolism, a high-fat feeding model of uncoupling protein 2 (UCP2) knockout mice was established to investigate the role of UCP2 and its upstream regulatory genes in glucose and lipid metabolism and to explore the role of UCP2 and its upstream regulatory genes in blood lipid metabolism. Polymorphisms of UCP2 and its upstream regulatory gene, Peroxisome Proliferator Activated Receptor y (PPAR y), were analyzed in a population with continuous glucose profile (healthy subjects - pre-diabetes mellitus - type 2 diabetes mellitus). The effects of telomere length (TL) and diet on mitochondrial-mediated glucose and lipid metabolism were analyzed. The pathogenesis of type 2 diabetes mellitus was discussed from genetic and environmental factors. Methods A total of 16 patients with mitochondrial diabetes mellitus were selected from the Department of Endocrinology, Peking Union Medical College Hospital from April 2007 to December 2015, and 16 patients with mitochondrial DNA 3243 AG mutation were recruited. A cohort of 599 people from rural communities in Beijing from March 2014 to January 2015 were involved in the establishment of type 2 diabetes management model. Direct sequencing (Sanger method) was used to detect gene mutation at 3243 locus. The peak ratio of base G/A was defined as the peak height of base G and the peak height of base A. Seven polymorphic sites (rs3856806, rs2920502, rs1702900, rs73021485, rs73813168, rs2920503, rs79310821) in the PPAR gamma domain were identified. Oxidative stress indices (TND, GR.8-oxo-dG, IL-6, IL-a) were used for the determination of PPAR gamma domain polymorphism. Animal studies: male UCP2-/-mice with C57BL/6 background and UCP2+/+ mice with C57BL/6 background of the same age. High-fat feeding for 16 weeks. Gene expression profiles in liver tissues were analyzed by whole-genome expression microarray (Affymetrix Mouse Gene ST 1.0 array). Results 1. Clinical characteristics of diabetic patients with mitochondrial DNA 3243 AG mutation Relationship between point and mutation heterogeneity and disease spectrum in 16 patients with mitochondrial diabetes mellitus (onset age: 35.0 + 14.6 years old) with a clear maternal genetic family history, leanness (BMI: 19.5 + 2.36 kg / m2), deafness involvement and high frequency domain. The peak G/A ratio of mitochondrial DNA 3243 AG mutation was negatively correlated with onset age (correlation coefficient r = - 0.841, P 0.0). 01). 2. Correlation analysis of mitochondrial DNA copy in peripheral blood and secretory function of islet beta cells stimulated by glucose Multivariate linear regression analysis showed that the decrease of mitochondrial DNA copy in peripheral blood increased the risk of impaired 8 cell function after glucose stimulation (DI30: beta = 0.104, P = 0.019; DI120: P = 0.116, P = 0.009). Significant negative correlation (OR: 0.468, 95% CI: 0.245-0.893, P = 0.021). 3. The role of UCP2 in glucose and wax metabolism and its metabolic pathway analysis in UCP2 - / - mice islet beta cell function and insulin sensitivity were better than those in UCP2 + / + mice, and the serum total cholesterol, triglycerides and free fatty acids in UCP2 - / - mice were significantly lower than those in UCP2 + / free fatty acids. According to the liver microarray analysis, the expression of seven genes in the PPAR signaling pathway was significantly up-regulated between UCP2-/- and UCP2+/+ groups, including PPAR gamma, Acsl3, Lpl, Mel, Scdl, Fads2.PPAR, and the other two isoforms, PPARck PPAR8, were not significantly different between UCP2-/-and UCP2+/+ groups. Allele G of PPAR gamma gene rs2920502 was the protective factor for abnormal glucose metabolism (allele OR: 0.818, 95% CI: 0.526-0.969, P = 0.042; genotype OR: 0.042). 715,95% CI: 0.527-0.97, P = 0.031), GG genotype TC, TG, LDL-C, TG / HDL-C were lower than GC, CC gene. Allele T at locus. rs3856806 was a risk factor for abnormal glucose metabolism (allele OR: 1.46, 95% CI: 1.055-2.017, P = 0.022; genotype OR: 1.58, 95% CI: 1.104-2.761, P = 0.032). The length of telomere in peripheral blood was significantly lower in type 2 diabetes mellitus than in normal control group, but there was no significant difference between type 2 diabetes mellitus and mitochondrial diabetes mellitus (mitochondrial diabetes vs type 2 diabetes vs type 2 diabetes vs normal control: 1.28 + 0.54 vs 1.14 + 0.43 vs 1.63 + 0.61, P = 0.000). There was no significant correlation between the telomere length of peripheral blood DNA and the G/A peak ratio of mitochondrial DNA 3243 mutation site (r = - 0.156, P = 0.646). 6. Dietary composition, carbohydrate composition ratio of peripheral blood DNA telomere length and blood glucose were significantly shorter in diabetes mellitus group than in normal control group (log (TL): vs diabetes mellitus in normal blood glucose group. There was no significant correlation between telomere length and dietary total energy intake or lipid/carbohydrate ratio. Multivariate linear regression analysis showed that soybean products, nuts, fish and algae were protective factors for telomere length, and sweet beverage was a risk factor. Factors (legume: beta = 0.105, P = 0.105, P = 0.018; nut: P = 0.110, P = 0.011: fish: bet = 0.118, P = 0.011: fish: fish: fish: bet = 0.118, P = 0.007: algae: bet = 0.116, P = 0.009). Dielipid, carbohydrate composition ratio and cereal, meat and TNF-alphawere positively correl (lipid: r = 0.119, P = 0.008; carbohydrate: r = 0.094, P = 0.043; gluten: gluten: r = 0.043; gluten: r = 0.043; gluten: r = 0.041, r = 0.091, r = 0.09Meat Algae, dairy intake and 8-oxo-dG were negatively correlated (algae: r = - 0.496, P = 0.001; dairy products: r = - 0.246, P = 0.046). Vegetable and fruit intake were positively correlated with GR (vegetable: r = 0.101, P = 0.034; fruit: r = 0.125, P = 0.045). 7. TG/HDL-C and TG could be used to predict insulin resistance (AUROC: 0.71, 95% CI: 0.66-0.75, P = 0.000; TG: AUROC: 0.71, 95% CI: 0.65-0.75, P = 0.000); TG / HDL-C and TG best cut-off values were 1.11, 1.33 mmol/L. In a 6-year cohort study of type 2 diabetes mellitus, Delta CP AUC (Delta CP AUC = baseline CP AUC - 6 years later CP AUC) was used to represent the changes of beta cell secretory function before and after 6 years (Delta CP AUC = baseline CP AUC - 6 years later CP AUC) and the delta CP AUC binary was used to determine the impairment of beta cell secretion. The subjects were divided into two groups: the group with slower decline in P-cell function and the group with faster decline in beta-cell function. The baseline log (TG)/HDL-C values of the group with faster decline in beta-cell function were higher than those of the group with slower decline (0.103.033 vs 0.083.030, P = 0.027). The baseline fasting of the group with faster decline in beta-cell function was higher than that of the group with slower decline in TG and area under the curve at 5 time points after standard meal. Conclusion 1. Early onset diabetes mellitus patients with maternal genetic family history, normal or thin BMI, deafness can strongly suggest the existence of mitochondrial diabetes mellitus. Direct sequencing of peripheral blood DNA to identify mitochondrial DNA 3243 AG mutation, its mutation G / A Peak ratio can predict the onset age and severity of mitochondrial disease. 2. In the population with continuous blood glucose profile, this study found for the first time that mitochondrial DNA copy was positively correlated with the early phase after glucose stimulation, and the overall insulin secretion function was significantly positively correlated. The effect on postprandial blood glucose was greater than that on fasting blood. 3. UCP2 deficiency through PPAR signaling pathway to improve insulin sensitivity and beta cell function to improve blood glucose, blood lipids, PPAR gamma polymorphism sites (rs2920502, rs3856806) is closely related to glucose and lipid metabolism, is an important gene regulating UCP2 expression under high-fat diet. 4. Telomere length shortening may be involved in the pathogenesis of diabetes, but Dietary components may influence telomere length by altering oxidative stress and inflammation. 5. In a population with a continuous blood glucose profile, TG/HDL-C was found to be a predictor of insulin resistance for the first time. TG/HDL-C was negatively correlated with fasting beta cell secretion. During the course of type 2 diabetes, the high Log (TG) /HDL-C value at baseline indicated that the progression of islet beta cell dysfunction was faster.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R587.1
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本文编号：2207865
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