['Cytokines stimulate nitric oxide production in pancreatic beta cells, leading to endoplasmic reticulum (ER) stress and apoptosis. Treatment of beta cells with glucose and NEFA induces nitric oxide synthase (NOS) as well as ER stress. However, the role of NO in glucolipotoxicity-induced ER stress in beta cells is not clear.', 'We studied the effect of high glucose and palmitate levels on NOS isoform production in rat and Psammomys obesus islets and in insulinoma-1E beta cells. The effects of neuronal NOS (nNOS) inhibition by small interfering RNA or by N (omega)-nitro-L-arginine methyl ester (L-NAME) on beta cell function, ER stress and apoptosis under conditions of glucolipotoxicity were investigated.', 'Overnight incubation of rat and P. obesus islets at 22.2 mmol/l glucose with 0.5 mmol/l palmitate induced the production of nNOS but not inducible NOS (iNOS), in contrast with the robust stimulation of iNOS by cytokines. NOS inhibition by L-NAME did not prevent the decrease in glucose-stimulated insulin secretion and proinsulin biosynthesis or the depletion of islet insulin content observed under conditions of glucolipotoxicity. Moreover, treatment of beta cells with palmitate and L-NAME together resulted in marked activation of the IRE1alpha and PERK pathways of the unfolded protein response. This was associated with increased JNK phosphorylation and apoptosis in islets and beta cells. Moreover, partial nNos knockdown increased JNK phosphorylation and CHOP production, leading to apoptosis.'] Does neuronal nitric oxide synthase protect the pancreatic beta cell from glucolipotoxicity-induced endoplasmic reticulum stress and apoptosis?