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. Corresponding author: Yasuo Terauchi, terauchi-tky{at}


The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in β-cells, 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 (βIRS-2-Tg) Akita mice showed less β-cell apoptosis than Akita mice. IRS-2–deficient islets were vulnerable, but βIRS-2-Tg islets were resistant to ER stress–induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress–related genes in an IRS-2–independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (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 14, 2013.

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