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}
  1. D.G. and S.B.-H. contributed equally to this study.


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.


  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

Articles citing this article

| Table of Contents

This Article

  1. Diabetes vol. 59 no. 9 2188-2197
  1. Online Appendix
  2. All Versions of this Article:
    1. db09-0890v1
    2. 59/9/2188 most recent