随着我国2型糖尿病发病率的不断攀升，我们迫切需要阐明其发病机理，并发现新的分子靶标以及开发新型治疗药物来对抗这类疾病。胰岛β细胞分泌胰岛素在调节全身糖稳态中具有至关重要的作用，而胰岛素分泌和胰岛素作用受损是2型糖尿病的基本生理特征，因此，深入的解析调控胰岛素分泌的分子机制对这类疾病的防治具有重要指导意义。申请人前期工作发现RalGAP复合体表达量在高脂饲喂小鼠的胰岛中显著增加，且胰岛β细胞中RalGAPβ亚基的的缺失大大的增加了葡萄糖刺激下胰岛素的分泌量，全身的葡萄糖清除能力和胰岛素敏感性也有显著提升。基于这些前期工作，本申请拟通过基因工程小鼠模型结合多种生物学手段，对RalGAP复合体调控胰岛素分泌分子作用机制展开深入研究。本项研究将为开发增强胰岛素分泌、治疗2型糖尿病的药物提供新的思路和理论基础。

With the rising incidence of type 2 diabetes in our country, we urgently need to clarify its pathogenesis, discover new molecular targets and develop new therapeutic drugs to combat such diseases. Islet β-cell secrets insulin which plays a vital role in regulating glucose homeostasis, and impaired insulin secretion and insulin action are the basic physiological characteristics of type 2 diabetes. Therefore, an in-depth analysis of the molecular mechanisms regulating insulin secretion has important guiding significance for the prevention and treatment of this disease. The applicant's previous work found that the expression of RalGAP complex was significantly increased in the islets of high-fat-fed mice, and the amount of insulin secretion was greatly increased with glucose stimulation when we knocked out RalGAPβ subunit in islet β cells. At the same time, the glucose clearance ability and insulin sensitivity of RalGAPβ knock-out mice also improved significantly. Based on these previous work, this application intends to conduct in-depth research on the molecular mechanism of RalGAP complex regulating insulin secretion through genetically engineered mouse models combined with multiple biological means. This research will provide new ideas and theoretical basis for the development of drugs that enhance insulin secretion and treat type 2 diabetes.