晚期糖基化终末产物在2型糖尿病中的作用及机制研究

Type 2 diabetes (T2D), a chronic metabolic disease caused by the interaction of gene and environment, brings about dramatic disease burdens to China. Advanced glycation end-products (AGEs) are formed via the nonenzymatic reaction of amino acids with sugars, termed the Maillard reaction. Although AGEs are ubiquitous compounds found in food, its hazard just been taken into account in recent years. The recent studies suggested that consumption of high amounts of AGEs is a determinant of inflammation, oxidative stress, and insulin resistance, which might play a driving role in the generation and development of T2D. However, the population-based study about the relationship between AGEs and T2D is still deficient. The dose-effect relation and the gene interaction of AGEs in the development of T2D are still unclear so far. In this project, based on the case-control study, we plan to explore the associations of circulating AGEs levels, genetic variations and their interaction on the risk of T2D, and use Mendelian randomization for etiological inferences. Moreover, we further verify the causal relationship between AGEs and T2D, and clarify the dose-response association based on the prospective cohort study. Additionally, lentivirus transfection cell model was established to deeply investigate the mechanism. Our research will not only provide scientific evidence for dietary exposure criteria of AGEs, but explore new biomarkers for T2D, which might contribute to early diagnosis and prevention of T2D.

2型糖尿病是一种由基因与环境共同作用的慢性代谢性疾病，给我国带来沉重的疾病负担。晚期糖基化终末产物是美拉德反应的产物，在食品中普遍存在，而其危害近几年才受到重视，研究认为其促进机体炎症和氧化应激，导致胰岛素抵抗，在糖尿病的发生发展中可能起到推动作用。然而晚期糖基化终末产物与2型糖尿病发病风险仍缺乏人群资料，其剂量-效应关系、基因交互作用目前仍不明确。本研究拟通过病例-对照研究，探索晚期糖基化终末产物与2型糖尿病的关联性，及其基因交互作用对2型糖尿病的影响，利用孟德尔随机化进行因果推断。基于前瞻性队列研究，进一步验证其与2型糖尿病发生的因果关系，阐明剂量-效应。利用慢病毒感染细胞构建模型，深入探讨晚期糖基化终末产物对2型糖尿病的致病机制，丰富理论研究。这些结果不仅有助于我国制定膳食中晚期糖基化终末产物暴露标准，而且有助于发现新的2型糖尿病生物标志物，对2型糖尿病的早期诊断和预防具有重要意义。

本项目旨在通过流行病学手段探讨人体晚期糖基化终末产物（AGEs）及其受体与2型糖尿病（T2DM）的关系，并通过动物实验初步探索膳食AGEs暴露对糖代谢的影响。由于AGEs种类较多，目前膳食数据库及调查问卷难以评估个体的AGEs负荷水平，因此本研究采用客观的生物标志物作为调查手段。我们首先建立了一套前处理简便、稳定可靠的基于超高效液相色谱串联质谱的AGEs定量检测方法，可同时定量检测人血浆多种AGEs水平。通过病例-对照的研究设计，探讨人体多种AGEs水平与新诊断T2DM的关联。进一步通过大型病例-对照研究进一步探讨了可溶性AGEs受体（sRAGE）水平与新诊断T2DM的关联，探索编码AGEs受体的基因AGER的单核苷酸多态性与sRAGE的交互效应在T2DM发生发展中的作用。最后，通过大鼠模型对膳食AGEs暴露与糖代谢紊乱及相关机制进行初步探索。本研究主要从人群层面发现AGEs暴露及其受体与T2DM存在显著相关，初步的动物实验证据也支持了人群的发现。系列研究成果将有助于糖尿病的膳食营养防控措施的建立，并为进一步探索潜在的干预物和干预靶点提供线索。