Glucokinase Activation Ameliorates ER Stress-Induced Apoptosis in Pancreatic Beta-Cells

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860754
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Yokohama City University
• Principal Investigator: SHIRAKAWA JUN 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (70625532)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 膵β細胞 / 糖尿病 / アポトーシス / 小胞体ストレス

Outline of Final Research Achievements

Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in beta-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 beta-cells. GKA administration improved beta-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. IRS-2-deficient islets were vulnerable, but bIRS-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 beta-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 beta-cells.

Free Research Field

糖尿病学