硒蛋白T干预细胞稳态调控胰岛素抵抗与2型糖尿病的作用机制研究

胰岛素抵抗是2型糖尿病的关键病因，并与氧化还原稳态及内质网稳态失衡密切相关。微量元素硒对2型糖尿病发生发展具有双向调控作用，已成为硒与健康领域新的研究热点。我们构建了世界首例硒蛋白T全身性基因敲除小鼠，并首次发现其胰岛素敏感性显著升高，但硒蛋白T调控胰岛素抵抗与2型糖尿病的分子机制尚不清楚。基于硒蛋白T对氧化还原稳态与内质网稳态的干预作用，本项目拟采用基因敲除﹑RNA干扰和过表达等技术，在细胞和动物模型中降低或升高硒蛋白T表达，探讨其基因敲除/基因敲低/过表达对胰岛素抵抗﹑瘦素信号通路﹑胰岛素敏感细胞中氧化还原稳态与内质网稳态及相关信号通路的调控作用及分子机制，揭示其关键信号途径与调控因子，阐明硒蛋白T调控胰岛素抵抗与2型糖尿病的作用机制。本研究有助于深化对硒与健康关系的正确认识，而且有可能为防治糖尿病及相关药物的研发提供科学依据和新的作用靶点，因而具有十分重要的科学意义和潜在的应用前景。

Insulin resistance is the key etiology of type 2 diabetes (T2D), and is closely related to the disturbance of redox homeostasis and endoplasmic reticulum (ER) homeostasis. Selenium, as a trace element, has dual regulatory effects on the onset and progression of T2D, which has become an emerging focus of research in the field of selenium and health. We have constructed the world’s first selenoprotein T (SelT) global knock-out mice, and have found for the first time that these mice exhibit significantly increased insulin sensitivity compared with wild type mice. However, the molecular mechanisms underlying regulation of insulin resistance and T2D by SelT remain elusive. In view of the regulatory role of SelT in redox homeostasis and ER homeostasis, we will use gene knock-out, RNA interference and gene overexpression technologies to decrease or increase SelT expression in cell cultures and animal models, and investigate the regulatory effects and the molecular mechanisms of SelT gene knock-out / knock down / overexpression on insulin resistance, leptin signal pathway, redox homeostasis, ER homeostasis and related signaling pathways in insulin-responsive cells, and reveal the key signaling pathways and regulators, eventually elucidating the molecular mechanisms underlying regulation of insulin resistance and T2D by SelT. The present study not only helps to deepen our understanding on the relationship between selenium and health, but also may provide scientific evidence and new targets for prevention and treatment of diabetes, and related drug development, and thus possesses great scientific significance and potential application prospects.