title: Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.
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.
authors.affiliation: Institute of Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sumara
authors.forename: Ivan
authors.initials: I
authors.lastname: Formentini
authors.forename: Stephan
authors.initials: S
authors.lastname: Collins
authors.forename: Izabela
authors.initials: I
authors.lastname: Sumara
authors.forename: Renata
authors.initials: R
authors.lastname: Windak
authors.forename: Bernd
authors.initials: B
authors.lastname: Bodenmiller
authors.forename: Reshma
authors.initials: R
authors.lastname: Ramracheya
authors.forename: Dorothée
authors.initials: D
authors.lastname: Caille
authors.forename: Huiping
authors.initials: H
authors.lastname: Jiang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Platt
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Rudolf
authors.initials: R
authors.lastname: Aebersold
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
mesh_terms: D000818:Animals; D005089:Exocytosis; D005260:Female; D005947:Glucose / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D007328:Insulin; D048292:Mitogen-Activated Protein Kinase 13; C089212:protein kinase D; D011493:Protein Kinase C; D010738:Type C Phospholipases; D005947:Glucose