Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic g cell exhaustion

Background: Diabetes mellitus is characterized by high blood glucose levels. Pancreatic 8 cell death contributes to type I and type 2 diabetes. Akita mice, which harbor a human permanent neonatal diabetes-linked mutation (Cys96Tyr) in the insulin gene, are well established as an animal model of diabetes caused by pancreatic beta cell exhaustion. Mutant Insulin 2 protein (Ins2(C96Y)) induces endoplasmic reticulum (ER) stress and pancreatic beta cell death in Akita mice, although the molecular mechanism of Ins(C96Y)-induced cell death remains unclear. Methods: We investigate the mechanisms of Ins2(C96Y)-induced pancreatic beta cell death in vitro and in vivo, using p38 inhibitor (SB203580), MIN6 cell (pancreatic beta cell line), Akita mice and apoptosis signal-regulating kinase 1 (ASK1) knockout mice. Results: The expression of Ins(C96Y) activated the ASK1-p38 pathway. Deletion of ASK1 mitigated Ins(C96Y)-induced pancreatic beta cell death and delayed the onset of diabetes in Akita mice. Moreover, p38 inhibitor suppressed Ins(C96Y)-induced MIN6 cell death. Conclusions: These findings suggest that ER stress-induced ASK1-p38 activation, which is triggered by the accumulation of Ins(C96Y), plays an important role in the pathogenesis of diabetes. General significance: Pancreatic beta cell death caused by insulin overload appears to be involved in the pathogenesis of type 1 and type 2 diabetes. Inhibition of the ASK1-p38 pathway may be an effective therapy for various types of diabetes. (C) 2013 Published by Elsevier B.V.