期刊
DIABETES
卷 62, 期 10, 页码 3448-3458出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-0052
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [21390282, 24390235]
- Japan Medical Association
- Japan Diabetes Foundation
- Uehara Memorial Foundation
- Naito Foundation
- Takeda Life Foundation
- Yokohama General Promotion Foundation
- Novo Nordisk Insulin Research Foundation
- Japan Foundation for Applied Enzymology
- Kanae Memorial Foundation
- Banyu Life Science Foundation International
- Grants-in-Aid for Scientific Research [23591316, 25670435, 21390282, 24390235] Funding Source: KAKEN
The derangement of endoplasmic reticulum (ER) homeostasis triggers -cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in -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 -cells. GKA administration improved -cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in -cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in -cell apoptosis, compared with Akita mice. -cell-specific IRS-2-overexpressing (IRS-2-Tg) Akita mice showed less -cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but IRS-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 -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 -cells.
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