Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size.

ABSTRACT: We examined the role of Rictor/mammalian target of rapamycin complex 2 (mTORC2), a key component of the phosphotidylinositol-3-kinase (PI3K)/mTORC2/AKT signaling pathway, in regulating both ?-cell mass and function.Mice with ?-cell-specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on ?-cell mass and glucose homeostasis.Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in ?-cell mass, ?-cell proliferation, pancreatic insulin content, and glucose-stimulated insulin secretion. Islets from these mice exhibited decreased AKT-S473 phosphorylation and increased abundance of FoxO1 and p27 proteins. Conversely, Pten null (?PtenKO) mice exhibited an increase in ?-cell mass caused by increased cellular proliferation and size. Although ?-cell mass was normal in mice lacking both Rictor and Pten (?DKO), their ?-cells were larger than those in the ?PtenKO mice. Even though the ?-cell proliferation rate in the ?DKO mice was lower than in the ?PtenKO mice, there was a 12-fold increase the phosphorylation of AKT-T308.PI3K/AKT signaling through mTORC2/pAKT-S473 plays a key role in maintaining normal ?-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between ?-cell proliferation and cell size in response to proliferative stimuli.

SUBMITTER: Gu Y 

PROVIDER: S-EPMC3046843 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other