Decreased IRS signaling impairs β-cell cycle progression and survival in transgenic mice overexpressing S6K in β-cells

  1. Ernesto Bernal-Mizrachi (ebernal{at}umich.edu)1
  1. 1 Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, Michigan 48105
  2. 2 Department of OB/GYN, Washington University School of Medicine, St Louis, Missouri 63110, USA

Abstract

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.

Footnotes

    • Received June 8, 2009.
    • Accepted June 25, 2010.