Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells.
OBJECTIVE
The purpose of this study was to evaluate the role of the S6K arm of mammalian target of rapamycin complex 1 (mTORC1) signaling in regulation of β-cell mass and function. Additionally, we aimed to delineate the importance of in vivo S6K activation in the regulation of insulin signaling and the extent to which alteration of insulin receptor substrate (IRS) signaling modulates β-cell mass and function.


METHODS
The current experiments describe the phenotype of transgenic mice overexpressing a constitutively active form of S6K under the control of the rat insulin promoter.


RESULTS
Activation of S6K signaling in these mice improved insulin secretion in the absence of changes in β-cell mass. The lack of β-cell mass expansion resulted from decreased G(1)-S progression and increased apoptosis. This phenotype was associated with increased p16 and p27 and decreased Cdk2 levels. The changes in cell cycle were accompanied by diminished survival signals because of impaired IRS/Akt signaling.


CONCLUSIONS
This work defines the importance of S6K in regulation of β-cell cycle, cell size, function, and survival. These experiments also demonstrate that in vivo downregulation of IRS signaling by TORC1/S6K induces β-cell insulin resistance, and that this mechanism could explain some of the abnormalities that ultimately result in β-cell failure and diabetes in conditions of nutrient overload.
Elghazi
Lynda
L
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, Michigan, USA.
Balcazar
Norman
N
Blandino-Rosano
Manuel
M
Cras-Méneur
Corentin
C
Fatrai
Szabolcs
S
Gould
Aaron P
AP
Chi
Maggie M
MM
Moley
Kelle H
KH
Bernal-Mizrachi
Ernesto
E
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D048429:Cell Size; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D011401:Promoter Regions, Genetic; D011506:Proteins; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D005947:Glucose