端粒长度与线粒体功能相关基因对2型糖尿病的预测作用和发病机制的研究

Type 2 diabetes has become a public health issue which influence the daily lives of the people.Telomere attrition and mutations of the UCP2 gene are related to the onset of this serious choronic disease.Telomere shortening is an important marker of biological aging in T2DM And kinds of mutation in UCP2 gene area may cause the change of mitochorondrial function that leads to islet beta cell dysfunction in T2DM individuals.The role of telomere atrrition and UCP2 gene polymorphism in T2DM pathogenesis is unclear.As it is hard to follow up the patients in different T2DM phases in long terms,the prospective research in this area is still limited.In this study,516 of T2DM,impired glucose tolerence and normal glucose tolerence individuals from 59 different familise have been followed for 13 years in peking union medical college hospital. The assessments of telomere attrition,UCP2 gene type and developement of T2DM in these people could provide important data in the analysis of the role of them in T2DM's pathogenesis.And the animal experiments of UCP2-knocked out mice will verify the data. The aim of the study is to look for the biological marker of T2DM oncet and provide experimental basis also clincal evidence in prognosis of T2DM.

2型糖尿病是影响人类健康的重大疾病之一，其发生与端粒长度缩短及UCP2基因变异有关。端粒长度缩短是2型糖尿病细胞老化的重要标志，UCP2基因突变亦可导致β细胞线粒体功能改变，引发2型糖尿病胰岛素分泌障碍。尽管现已明确端粒长度缩短、UCP2基因多态性均分别与β细胞线粒体损伤有关，但两者对2型糖尿病发生的预测价值及发病机制的前瞻性研究较少。本研究在13年前收集的2型糖尿病、IGT及正常人的59个家系516人、12例线粒体糖尿病家系的基础上，可对此人群进行13年前后血糖转归状况的评估，并检测及分析端粒长度、UCP2基因型，探讨端粒长度缩短、UCP2基因型对2型糖尿病的预测作用，利用UCP2基因敲除大鼠进一步对三者之间的发病机制进行验证，为2型糖尿病发病机制及预测寻找重要生物标志物，并为中国人群的2型糖尿病预测提供实验基础及临床证据。

线粒体基因突变与线粒体拷贝量减少共同参与线粒体功能障碍及糖尿病的发生。本研究首先从线粒体单基因突变的线粒体糖尿病家系入手，探讨线粒体功能障碍、端粒长度改变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，来探索UCP2在糖脂代谢调控中的作用及机制。在血糖谱连续的人群中，探寻饮食结构对线粒体功能及对端粒长度的影响，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指标。通过2型糖尿病随访队列研究，探究端粒缩短对非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）的预测作用。. 本课题发现或揭示了：.1）早发糖尿病伴母系遗传家族史、BMI正常或偏瘦、耳聋强烈提示线粒体糖尿病。检测外周血线粒体DNA 3243 A>G突变有助诊断，其突变G/A峰值与发病年龄显著负相关。.2）在血脂谱连续人群，本研究首次发现，线粒体DNA拷贝量与葡萄糖刺激的早相、总体胰岛素分泌呈显著正相关。.3）UCP2缺乏通过PPAR信号通路提高胰岛素敏感性和β细胞功能来改善糖脂代谢。.4）端粒长度缩短可能参与糖尿病的发病机制；饮食成分可能通过氧化应激、炎症状态影响端粒长度。.5）在血脂谱连续人群，本研究首次发现，血脂比TG/HDL-C可作为胰岛素抵抗的预测指标；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。.6）超声肝肾回声比值及肝脏回声衰减系数可定量评估脂肪肝程度；2型糖尿病病程中发生非酒精性脂肪肝（NAFLD）者端粒长度较短，且早期即出现较严重的胰岛素抵抗。