Decreased IRS signaling impairs β-cell cycle progression and survival in transgenic mice overexpressing S6K in β-cells
Objectives: The purpose of this study was to evaluate the role of the S6K arm of mTORC1 signaling in regulation of β-cell mass and function. Additionally, we delineate the importance of in vivo S6K activation in the regulation of insulin signaling and the extent to which alteration of IRS signaling modulates β-cell mass and function.
Research design and 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 improves insulin secretion in the absence of changes in β-cell mass. The lack of β-cell mass expansion resulted from decreased G1-S progression and increased apoptosis. This phenotype was associated to increased p16 and p27 and decreased Cdk2 levels. The changes in cell cycle were accompanied by diminished survival signals as a consequence of impaired IRS/Akt signaling.
Conclusions: The current work defines the importance of S6K in regulation of β-cell cycle, cell size, function and survival. These experiments also demonstrate that in vivo down-regulation 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.
- Received June 8, 2009.
- Accepted June 25, 2010.
- Copyright © American Diabetes Association