Abstract：
:Dysfunction and loss of insulin-producing pancreatic beta cells represent hallmarks of diabetes mellitus. Here, we show that mice lacking the mitogen-activated protein kinase (MAPK) p38delta display improved glucose tolerance due to enhanced insulin secretion from pancreatic beta cells. Deletion of p38delta results in pronounced activation of protein kinase D (PKD), the latter of which we have identified as a pivotal regulator of stimulated insulin exocytosis. p38delta catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. In addition, p38delta null mice are protected against high-fat-feeding-induced insulin resistance and oxidative stress-mediated beta cell failure. Inhibition of PKD1 reverses enhanced insulin secretion from p38delta-deficient islets and glucose tolerance in p38delta null mice as well as their susceptibility to oxidative stress. In conclusion, the p38delta-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic beta cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.
journal_name
Celljournal_title
Cellauthors
Sumara G,Formentini I,Collins S,Sumara I,Windak R,Bodenmiller B,Ramracheya R,Caille D,Jiang H,Platt KA,Meda P,Aebersold R,Rorsman P,Ricci Rdoi
10.1016/j.cell.2008.11.018subject
Has Abstractpub_date
2009-01-23 00:00:00pages
235-48issue
2eissn
0092-8674issn
1097-4172pii
S0092-8674(08)01493-1journal_volume
136pub_type
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