Glucose potentiates interleukin-1 beta (IL-1 beta)-induced p38 mitogen-activated protein kinase activity in rat pancreatic islets of Langerhans

The cytokine interleukin-1 beta (IL-1 beta) is cytotoxic to rat pancreatic beta -cells and has been implicated in the pathogenesis of insulin-dependen t diabetes mellitus. IL-1 beta causes expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). NO may be the mediator of the cytotoxic effect of IL-1 beta in rat islets and beta -cell lines. G lucose has been shown to modulate the effects of IL-1 beta on accumulated i nsulin release and potentiate NO production in rat islets, but the biochemi cal mechanism is unknown. IL-1 beta activates the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and c-jun NH2-terminal kinase (JNK) in rat islets and beta -cells. Glucose may modulate MAPK activity although contrasting data have been published. The aim of this study was to investigate whether glucose potentiated IL-1 b eta -induced p38 and ERK1/2 activity in rat islets. It was shown that gluco se alone increased the phosphorylation of the MAPK substrates Elk-l and act ivating transcription factor 2 (ATF2). D-glucose potentiated the p38 activi ty induced by a low concentration of IL-1 beta, whereas no effect was seen at high concentrations of IL-1 beta. Inhibition of p38 activity prevented I L-1 beta -induced nitrite production in the presence of D-glucose. We concl ude that IL-1 beta -induced NO production in the presence of glucose is sig nalled by the p38 pathway.