A 1‐hour pulse with IL‐1β induces formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: evidence for a tyrosine kinase signaling mechanism

Nitric oxide has been implicated as the effector molecule that mediates interlcukin‐1 β (IL‐1 β )‐in‐duced inhibition of glucose‐stimulated insulin secretion by rat islets. Brief exposures of islets (1 h) to IL‐1 β have been shown to inhibit glucose‐stimulated insulin secretion at 8 or 18 h after removal of this cytokine. The purpose of this investigation was to determine if brief exposures of islets to IL‐1 β are sufficient to induce the formation of nitric oxide and to examine the signaling process associated with IL‐1 β ‐induced expression of nitric oxide synthase. We demonstrate that a 1‐h pretreatment of islets with IL‐1 β followed by an 8‐h incubation in the absence of this cytokine results in inhibition of glucose‐stimulated insulin secretion (50%), which is completely prevented by pretreatment of islets with the nitric oxide synthase inhibitor N G ‐monomethyl‐L‐arginine (NMMA). The production of nitric oxide by islets under these pulse conditions is demonstrated by IL‐1 β ‐induced nitrite and electron paramagnetic resonance‐detectable iron‐nitrosyl complex formation, both of which are prevented by NMMA. IL‐1 β initiates a signal transduction process resulting in the expression of nitric oxide synthase. The signaling process appears to require the activation of a tyrosine kinase, since the tyrosine kinase inhibitor genistein prevents both IL‐1 β ‐induced inhibition of insulin secretion by islets and formation of nitric oxide by the insulinoma cell line RINm5F. These results show that short exposures of islets to IL‐1 β are sufficient to induce the formation of nitric oxide resulting in inhibition of glucose‐stimulated insulin secretion and that a tyrosine kinase may participate in the early signaling events required for IL‐1 β to induce the expression of nitric oxide synthase.— Corbett, J. A.; Sweetland, M. A.; Lancaster, J. R., Jr.; McDaniel, M. L. A 1‐hour pulse with IL‐1 β induces formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: evidence for a tyrosine kinase signaling mechanism. FASEB J. 7: 369‐374; 1993.