| First Author | Shirakawa J | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 10 | Pages | 3448-58 |
| PubMed ID | 23801577 | Mgi Jnum | J:208951 |
| Mgi Id | MGI:5565426 | Doi | 10.2337/db13-0052 |
| Citation | Shirakawa J, et al. (2013) Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic beta-cells. Diabetes 62(10):3448-58 |
| abstractText | The derangement of endoplasmic reticulum (ER) homeostasis triggers beta-cell apoptosis, leading to diabetes. 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. GKA increased the expression of IRS-2 in beta-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2-deficient Akita mice exhibited an increase in beta-cell apoptosis, compared with Akita mice. beta-cell-specific IRS-2-overexpressing (betaIRS-2-Tg) Akita mice showed less beta-cell apoptosis than Akita mice. IRS-2-deficient islets were vulnerable, but betaIRS-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. |
