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Biochim Biophys Acta. 2013 Jun;1830(6):3656-63. doi: 10.1016/j.bbagen.2013.01.029. Epub 2013 Feb 15.

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

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  • 1The University of Tokyo, Bunkyo-ku, Tokyo, Japan.



Diabetes mellitus is characterized by high blood glucose levels. Pancreatic ß cell death contributes to type 1 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 ß cell exhaustion. Mutant Insulin 2 protein (Ins2(C96Y)) induces endoplasmic reticulum (ER) stress and pancreatic ß cell death in Akita mice, although the molecular mechanism of Ins(C96Y)-induced cell death remains unclear.


We investigate the mechanisms of Ins2(C96Y)-induced pancreatic ß cell death in vitro and in vivo, using p38 inhibitor (SB203580), MIN6 cell (pancreatic ß cell line), Akita mice and apoptosis signal-regulating kinase 1 (ASK1) knockout mice.


The expression of Ins(C96Y) activated the ASK1-p38 pathway. Deletion of ASK1 mitigated Ins(C96Y)-induced pancreatic ß cell death and delayed the onset of diabetes in Akita mice. Moreover, p38 inhibitor suppressed Ins(C96Y)-induced MIN6 cell death.


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.


Pancreatic ß 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.

Copyright © 2013. Published by Elsevier B.V.

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