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

  1. Yehiel Zick (yehiel.zick{at}
  1. From 1The Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, and
  2. 2The Department of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel


Objective. Cellular stress and pro-inflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signalling. Here we examined the role of Ser phosphorylation of IRS-2 in mediating the inhibitory effects of pro-inflammatory 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 Streptozotocin-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 post-transplantation.

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


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