Rictor/mTORC2 is essential for maintaining a balance between beta-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 β-cell mass and function.


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.
Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Yanyun
Y
Gu
Jill
J
Lindner
Anil
A
Kumar
Weiping
W
Yuan
Mark A
MA
Magnuson
D000483:Alleles; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D048429:Cell Size; D005455:Fluorescent Antibody Technique; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D002352:Carrier Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose
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