硒蛋白S代谢失衡诱导胰岛素抵抗和2型糖尿病的作用机制

Diabetes is a kind of major disease affecting human health. Oxidative stress, inflammation and endoplasmic reticulum (ER) stress are involved in the generation and progress of insulin resistance and type 2 diabetes. Previous studies and our recent study found that selenoprotein S (SelS) promotion or depression could induce insulin resistance in vitro. However, the induction of insulin resistance and type 2 diabetes by a disturbance of SelS homeostasis has not been validated in vivo, and the underlying molecular mechanisms remain unclear. In view of the regulation of oxidative stress, inflammation and ER stress by SelS, we will increase or decrease SelS expression in cells and animals by gene overexpression, RNAi and model animal research, and investigate the molecular mechanisms underlying the effects of a disturbance of SelS homeostasis on insulin signaling pathway, oxidative stress, inflammation and ER stress in insulin-responsive cells/tissues, to elucidate the molecular mechanisms underlying the induction of insulin resistance and type 2 diabetes by a disturbance of SelS homeostasis. 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.

糖尿病是影响人类健康的重大疾病，氧化应激、炎症和内质网应激可促进胰岛素抵抗和2型糖尿病的发生发展。以往研究和我们的近期研究发现，硒蛋白S表达过高或过低均可诱导体外胰岛素抵抗；但硒蛋白S代谢失衡诱导胰岛素抵抗和2型糖尿病的作用尚未在体内证实，而且其分子机制尚不清楚。基于硒蛋白S对氧化应激、炎症和内质网应激的调节作用，本项目拟采用基因过表达、RNA干扰和模式动物研究等手段，通过在细胞和动物水平上升高或降低硒蛋白S表达，探讨硒蛋白S代谢失衡对胰岛素敏感细胞/组织中胰岛素信号通路及氧化应激、炎症、内质网应激的影响规律及其分子机制，阐明硒蛋白S代谢失衡诱导胰岛素抵抗和2型糖尿病的作用机制。本研究不仅有助于深化人类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。

糖尿病是影响人类健康的重大疾病，以往研究发现硒蛋白S表达过高可诱导体外胰岛素抵抗，可能与2型糖尿病的发生发展密切相关。然而，硒蛋白S代谢失衡诱导胰岛素抵抗和2型糖尿病的作用尚未在体内证实，而且其分子机制尚不清楚。本项目采用体内外RNA干扰和基因敲除动物研究等手段，在HepG2细胞、基因敲除与饮食诱导2型糖尿病动物模型中降低硒蛋白S表达，探讨硒蛋白S基因敲减对糖脂代谢稳态、胰岛素敏感细胞/组织中胰岛素信号通路及相关信号通路的影响规律及其分子机制。研究结果表明硒蛋白S基因敲减有效的改善了胰岛素抵抗、2型糖尿病与肝脏脂肪变性，该作用依赖于AMPK活性，从而阐明了硒蛋白S代谢失衡诱导胰岛素抵抗与2型糖尿病的作用机制。本研究不仅有助于深化人类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。由于本课题组在该领域的重要发现，本项目负责人受邀为Free Radical Biology and Medicine撰写了相关的综述，被该期刊选为“亮点论文”并进行专题述评。