Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Improves β-Cell Function Under Stress

  1. Yehiel Zick1
  1. 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel;
  2. 2Department of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  1. Corresponding author: Yehiel Zick, yehiel.zick{at}weizmann.ac.il.
  1. D.G. and S.B.-H. contributed equally to this study.

Abstract

OBJECTIVE Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signaling. Here, we examined the role of Ser phosphorylation of IRS-2 in mediating the inhibitory effects of proinflammatory cytokines and cellular stress on β-cell function.

RESEARCH DESIGN AND METHODS Five potential inhibitory Ser sites located proximally to the P-Tyr binding domain of IRS-2 were mutated to Ala. These IRS-2 mutants, denoted IRS-25A, and their wild-type controls (IRS-2WT) were introduced into adenoviral constructs that were infected into Min6 cells or into cultured murine islets.

RESULTS When expressed in cultured mouse islets, IRS-25A was better than IRS-2WT in protecting β-cells from apoptosis induced by a combination of IL-1β, IFN-γ, TNF-α, and Fas ligand. Cytokine-treated islets expressing IRS25A secreted significantly more insulin in response to glucose than did islets expressing IRS-2WT. This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed IRS-25A. Accordingly, transplantation of 200 islets expressing IRS25A into STZ-induced diabetic mice restored their ability to respond to a glucose load similar to naïve mice. In contrast, mice transplanted with islets expressing IRS2WT maintained sustained hyperglycemia 3 days after transplantation.

CONCLUSIONS Elimination of a physiological negative feedback control mechanism along the insulin-signaling pathway that involves Ser/Thr phosphorylation of IRS-2 affords protection against the adverse effects of proinflammatory cytokines and improves β-cell function under stress. Genetic approaches that promote IRS25A expression in pancreatic β-cells, therefore, could be considered a rational treatment against β-cell failure after islet transplantation.

Footnotes

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  • Received June 16, 2009.
  • Accepted June 3, 2010.

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  1. Diabetes vol. 59 no. 9 2188-2197
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