小G蛋白家族分子 Rheb1（Ras Homolog Enriched in Brain 1）属于RAS家族的重要基因,其主要功能被认为是通过直接激活mTORC1信号通路调控细胞增殖、生长和再生。Rheb1是否直接影响胰岛素分泌目前尚未可知。我们前期数据显示在胰岛β细胞中敲除Rheb1基因抑制GLUT2表达，导致胰岛β细胞胰岛素分泌下降。一个重要发现是，Rheb1对于GLUT2的调控可能不依赖于mTORC1信号通路。本研究在国内外首次利用胰岛β细胞特异性 Rheb1 基因敲除和过表达小鼠模型（下文称“bRheb1KO小鼠”和“bRheb1Tg小鼠”）以及独特的Rheb1敲除/过表达β细胞模型和人胰岛模型，从在体、细胞和分子三个不同层面系统研究Rheb1对胰岛β细胞胰岛素分泌的调控作用，阐明胰岛素分泌调控的新机制，为糖尿病的预防和治疗提供新的靶点和思路。

Rheb1, known as Ras homolog enriched in brain 1, is a GTP-binding protein that is ubiquitously expressed in the cells/tissues of humans and other mammals. The protein is mainly involved in the mTORC1 signaling pathway and plays important roles in the regulation of cellular proliferation, growth and cell cycle. Our preliminary data showed that ablation of Rheb1 in pancreatic β cells decreased insulin secretion and down-regulated GLUT2 expression in pancreatic β cells, which effects might be independent of mTOR. In this project, we will use pancreatic β cell-specific knockout/overexpression of Rheb1 models to demonstrate the detailed mechanism by which Rheb1 regulates insulin secretion and GLUT2 expression. We will use different research strategies such as Rheb1 konckout/overexpression β cell lines, pancreatic β cell-specific Rheb1 knockout/transgenic mice and human islets to further study the mechanism Rheb1-GLUT2 regulation. We believe that our study will provide important information on the regulation of pancreatic β cell function and insulin secretion, which could reveal potential new strategies and new drug targets for the clinical treatment of diabetes.