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Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.

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.

Pubmed ID: 19135240


  • 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 R



Publication Data

January 23, 2009

Associated Grants

  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Exocytosis
  • Female
  • Glucose
  • Golgi Apparatus
  • Insulin
  • Insulin-Secreting Cells
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 13
  • Protein Kinase C
  • Type C Phospholipases