Rictor/mTORC2 Is Essential for Maintaining a Balance Between β-Cell Proliferation and Cell Size

OBJECTIVE-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 beta-cell mass and function. RESEARCH DESIGN AND METHODS-Mice with beta-cell-specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on beta-cell mass and glucose homeostasis. RESULTS-Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in beta-cell mass, beta-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 (beta PtenKO) mice exhibited an increase in beta-cell mass caused by increased cellular proliferation and size. Although beta-cell mass was normal in mice lacking both Rictor and Pen (beta DKO), their beta-cells were larger than those in the beta PtenKO mice. Even though the beta-cell proliferation rate in the beta DKO mice was lower than in the beta Pten,KO mice, there was a 12-fold increase the phosphorylation of AKT-T308. CONCLUSIONS-PI3K/AKT signaling through mTORC2/pAKT-S473 plays a key role in maintaining normal beta-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between beta-cell proliferation and cell size in response to proliferative stimuli. Diabetes 60:827-837, 2011