Cytokine-Induced Inhibition of Insulin Release from Mouse Pancreatic β-Cells Deficient in Inducible Nitric Oxide Synthase

Abstract

Cytokines may participate in islet destruction during the development of type 1 diabetes. Expression of inducible nitric oxide synthase (iNOS) and subsequent NO formation induced by IL-1β or (IL-1β + IFN-γ) may impair islet function in rodent islets. Inhibition of iNOS or a deletion of the iNOS gene (iNOS −/− mice) protects against cytokine-induced β-cell suppression, although cytokines might also induce NO-independent impairment. Presently, we exposed wild-type (wt, C57BL/6 × 129SvEv) and iNOS −/− islets to IL-1β (25 U/ml) and (IL-1β (25 U/ml) + IFN-γ (1000 U/ml)) for 48 h. IL-1β and (IL-1β + IFN-γ) induced a significant increase in NO formation in wt but not in iNOS −/− islets. Both IL-1β and (IL-1β + IFN-γ) impaired glucose-stimulated insulin release and reduced the insulin content of wt islets, while (IL-1β + IFN-γ) reduced glucose oxidation rates and cell viability. IL-1β exposure to iNOS −/− islets impaired glucose-stimulated insulin release, increased insulin accumulation and reduced the insulin content, without any increase in cell death. Exposure to (IL-1β + IFN-γ) had no effect on iNOS −/− islets except reducing the insulin content. Our data suggest that IL-1β may inhibit glucose-stimulated insulin release by pathways that are not NO-dependent and not related to glucose metabolism or cell death.