Regulation of PKD by the MAPK p38δ in Insulin Secretion and Glucose Homeostasis

Abstract

SummaryDysfunction and loss of insulin-producing pancreatic β cells represent hallmarks of diabetes mellitus. Here, we show that mice lacking the mitogen-activated protein kinase (MAPK) p38δ display improved glucose tolerance due to enhanced insulin secretion from pancreatic β cells. Deletion of p38δ results in pronounced activation of protein kinase D (PKD), the latter of which we have identified as a pivotal regulator of stimulated insulin exocytosis. p38δ catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. In addition, p38δ null mice are protected against high-fat-feeding-induced insulin resistance and oxidative stress-mediated β cell failure. Inhibition of PKD1 reverses enhanced insulin secretion from p38δ-deficient islets and glucose tolerance in p38δ null mice as well as their susceptibility to oxidative stress. In conclusion, the p38δ-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic β cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.

Regulation of Golgi structure and secretion by receptor-induced G protein βγ complex translocation

“…Consistent with a role for the GPCR-induced fragmentation changes in secretion observed here, Golgi fragmentation has been observed in secretory pancreatic acinar cells activated with a GPCR agonist, cholecystokinin (28). Our results are also consistent with the ablation of p38Δ enzyme in pancreatic β cells, which leads to overactivation of PKD, increased insulin secretion, and fragmentation of the entire Golgi complex (8). The receptor-induced translocation of the G protein βγ complex may thus serve as an unexpected mechanism at the basis of the regulation of secretion.…”

“…S1), indicating alteration of the entire Golgi structure. This exaggerated response is similar to the breakdown of the entire Golgi complex that has previously been seen when Golgi protein kinase D (PKD) was overly activated (8,9). When distribution of TGN46 and GM130 was analyzed in cells in which γ11 was not transfected, receptor activation had no effect, showing that γ11 is necessary for fragmentation.…”

“…The specific mechanisms at the basis of M3 regulation of secretion have not been clear. Recent evidence suggests that this M3 stimulation of insulin secretion is mediated in part by PKD-mediated vesicle formation from the Golgi complex (8). Here, we examined the impact of M3-muscarinic-receptor-activated G protein βγ translocation on the Golgi complex structure and secretion of insulin.…”

MAPK signaling in inflammation-associated cancer development

“…Mice with disruption of other p38 isoforms are viable and fertile. Recently, it was reported that mice lacking p38g showed defects in insulin secretion in pancreatic β cells (Sumara et al, 2009). p38α is a serine/threonine kinase which rapidly responds to stresses such as endotoxic lipopolysaccharide (LPS) and heat shock (Han and Sun, 2007;Hui et al, 2007b). p38α phosphorylation is regulated by MKK3 and MKK6, which are activated by upstream kinases, such as MTK1 and ASK1 (Han and Sun, 2007;Hui et al, 2007b).…”

p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

“…Recent reports implicate p38γ and p38δ in metabolic diseases, cancer, and tissue regeneration, raising interest in this pathway as a therapeutic target for drugs. p38δ regulates insulin secretion and survival of pancreatic β-cells, implying a pivotal role for this kinase in diabetes (12). Moreover, studies in mice suggest that p38γ blocks premature differentiation of satellite cells, a skeletal muscle stem-cell population that participates in adult muscle regeneration (13).…”