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

Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA
Diabetes. 2011 60 (3): 827-37

PMID: 21266327 · PMCID: PMC3046843 · DOI:10.2337/db10-1194

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 β-cell mass and function.

RESEARCH DESIGN AND METHODS - Mice with β-cell-specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on β-cell mass and glucose homeostasis.

RESULTS - Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in β-cell mass, β-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 (βPtenKO) mice exhibited an increase in β-cell mass caused by increased cellular proliferation and size. Although β-cell mass was normal in mice lacking both Rictor and Pten (βDKO), their β-cells were larger than those in the βPtenKO mice. Even though the β-cell proliferation rate in the βDKO mice was lower than in the βPtenKO 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 β-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between β-cell proliferation and cell size in response to proliferative stimuli.

MeSH Terms (22)

Alleles Analysis of Variance Animals Apoptosis Blotting, Western Carrier Proteins Cell Proliferation Cell Size Fluorescent Antibody Technique Genotype Glucose Glucose Intolerance Hyperglycemia Insulin-Secreting Cells Mice Mice, Knockout Phosphorylation Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Rapamycin-Insensitive Companion of mTOR Protein Reverse Transcriptase Polymerase Chain Reaction Signal Transduction

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