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.
Sumara
Grzegorz
G
Institute of Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland.
Formentini
Ivan
I
Collins
Stephan
S
Sumara
Izabela
I
Windak
Renata
R
Bodenmiller
Bernd
B
Ramracheya
Reshma
R
Caille
Dorothée
D
Jiang
Huiping
H
Platt
Kenneth A
KA
Meda
Paolo
P
Aebersold
Rudolf
R
Rorsman
Patrik
P
Ricci
Romeo
R
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
D007328:Insulin; D048292:Mitogen-Activated Protein Kinase 13; C089212:protein kinase D; D011493:Protein Kinase C; D010738:Type C Phospholipases; D005947:Glucose