Yang Yan, Cai Zixin, Pan Zhenhong, Liu Fen, Li Dandan, Ji Yujiao, Zhong Jiaxin, Luo Hairong, Hu Shanbiao, Song Lei, Yu Shaojie, Li Ting, Li Jiequn, Ma Xianhua, Zhang Weiping, Zhou Zhiguang, Liu Feng, Zhang Jingjing
National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
Metabolism. 2021 Oct;123:154863. doi: 10.1016/j.metabol.2021.154863. Epub 2021 Aug 8.
Reduced β-cell mass and impaired β-cell function are primary causes of all types of diabetes. However, the intrinsic molecular mechanism that regulates β-cell growth and function remains elusive. Here, we demonstrate that the small GTPase Rheb1 is a critical regulator of glucose-stimulated insulin secretion (GSIS) in β-cells. Rheb1 was highly expressed in mouse and human islets. In addition, β-cell-specific knockout of Rheb1 reduced the β-cell size and mass by suppressing β-cell proliferation and increasing β-cell apoptosis. However, tamoxifen-induced deletion of Rheb1 in β-cells had no significant effect on β-cell mass and size but significantly impaired GSIS. Rheb1 facilitates GSIS in human or mouse islets by upregulating GLUT1 or GLUT2 expression, respectively, in a mTORC1 signaling pathway-dependent manner. Our findings reveal a critical role of Rheb1 in regulating GSIS in β-cells and identified a new target for the therapeutic treatment of diabetes mellitus.
β细胞数量减少和β细胞功能受损是所有类型糖尿病的主要原因。然而，调节β细胞生长和功能的内在分子机制仍不清楚。在此，我们证明小GTP酶Rheb1是β细胞中葡萄糖刺激的胰岛素分泌（GSIS）的关键调节因子。Rheb1在小鼠和人类胰岛中高表达。此外，Rheb1的β细胞特异性敲除通过抑制β细胞增殖和增加β细胞凋亡来减少β细胞大小和数量。然而，他莫昔芬诱导的β细胞中Rheb1缺失对β细胞数量和大小没有显著影响，但显著损害了GSIS。Rheb1分别通过以mTORC1信号通路依赖的方式上调GLUT1或GLUT2的表达来促进人类或小鼠胰岛中的GSIS。我们的研究结果揭示了Rheb1在调节β细胞GSIS中的关键作用，并确定了糖尿病治疗的新靶点。
