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

Cell. 2009 Jan 23;136(2):235-48. doi: 10.1016/j.cell.2008.11.018. Epub 2009 Jan 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Insulin
  • Mitogen-Activated Protein Kinase 13
  • protein kinase D
  • Protein Kinase C
  • Type C Phospholipases
  • Glucose