Critical roles for the TSC-mTOR pathway in β-cell function

Mori H, Inoki K, Opland D, Munzberg H, Villanueva EC, Faouzi M, Ikenoue T, Kwiatkowski DJ, MacDougald OA, Myers MG Jr, Guan KL. Critical roles for the TSC-mTOR pathway in beta-cell function. Am J Physiol Endocrinol Metab 297: E1013-E1022, 2009. First published August 18, 2009; doi: 10.1152/ajpendo.00262.2009.-TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in beta-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic beta-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function beta-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of beta-cell size, mass, and insulin production but not determinants of beta-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in beta-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in beta-cells. Thus, mTOR promulgates a dominant signal to promote beta-cell/islet size and insulin production, and this pathway is crucial for beta-cell function and glycemic control.