Rheb1 promotes glucose-stimulated insulin secretion in human and mouse β-cells by upregulating GLUT expression

Reduced beta-cell mass and impaired beta-cell function are primary causes of all types of diabetes. However, the intrinsic molecular mechanism that regulates beta-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 beta-cells. Rheb1 was highly expressed in mouse and human islets. In addition, beta-cell-specific knockout of Rheb1 reduced the beta-cell size and mass by suppressing beta-cell proliferation and increasing beta-cell apoptosis. However, tamoxifen-induced deletion of Rheb1 in beta-cells had no significant effect on beta-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 beta-cells and identified a new target for the therapeutic treatment of diabetes mellitus. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).