Glucokinase activation ameliorates ER stress-induced apoptosis in pancreatic ?-cells.

ABSTRACT: 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.

SUBMITTER: Shirakawa J 

PROVIDER: S-EPMC3781485 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature