Cytokine-induced inhibition of insulin release from mouse pancreatic beta-cells deficient in inducible nitric oxide synthase

Cytokines may participate in islet destruction during the development of ty pe 1 diabetes. Expression of inducible nitric oxide synthase (iNOS) and sub sequent NO formation induced by IL-1 beta or (IL-1 beta + IFN-gamma) may im pair islet function in rodent islets, Inhibition of iNOS or a deletion of t he iNOS gene (iNOS -/- mice) protects against cytokine-induced beta -cell s uppression, although cytokines might also induce NO-independent impairment. Presently, we exposed wild-type (wt, C57BL/6 x 129SvEv) and iNOS -/- islet s to IL-1 beta (25 U/ml) and (IL-1 beta (25 U/ml) + IFN-gamma (1000 U/ml)) for 48 h, IL-1 beta and (IL-1 beta + IFN-gamma) induced a significant incre ase in NO formation in wt but not in iNOS -/- islets, Both IL-1 beta and (I L-1 beta + IFN-gamma) impaired glucose-stimulated insulin release and reduc ed the insulin content of wt islets, while (IL-1 beta + IFN-gamma) reduced glucose oxidation rates and cell viability. IL-1 beta exposure to NOS -/- i slets impaired glucose-stimulated insulin release, increased insulin accumu lation and reduced the insulin content, without any increase in cell death. Exposure to (IL-1 beta + IFN-gamma) had no effect on iNOS -/- islets excep t reducing the insulin content. Our data suggest that IL-1 beta may inhibit glucose-stimulated insulin release by pathways that are not NO-dependent a nd not related to glucose metabolism or cell death. (C) 2001 Academic Press .