Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO block cytokine induced NOX-1. ► Integrated pathway of inflammatory cytokine-induced beta cell dysfunction identified. Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p