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

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.