Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic β cells

  1. Yasuo Terauchi1
  1. 1Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
  2. 2Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  1. Address Correspondence to Yasuo Terauchi E-mail: terauchi-tky{at}


The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell apoptosis, leading to diabetes. Glucokinase up-regulates IRS-2 expression in β cell, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in β cells. GKA administration improved β-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in β cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in β-cell apoptosis, compared with Akita mice. β-cell-specific IRS-2-overexpressing (βIRS2Tg) Akita mice showed less β-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but βIRS2Tg islets were resistant to ER stress-induced apoptosis. Meanwhile, GKA regulated the expressions of CHOP and other ER stress-related genes in an IRS-2-independent fashion in islets. GKA suppressed the expressions of CHOP and Bax and protected against β-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2-independent manner. Taken together, GKA ameliorated ER stress-mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2-independent control of apoptosis in β cells.

  • Received January 12, 2013.
  • Accepted June 6, 2013.

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