Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets

In rodent islets, exposure to interleukin-1β (IL-1β) and interferon-γ (IFN-γ) induces expression of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) formation, which may inhibit islet function. However, cytokines may also induce NO-independent islet suppression. The present aim was to investigate the effect of cytokine exposure to iNOS deficient (iNOS−/−) mouse islets on various islet functions. Islets from iNOS−/− and wt mice exposed to IL-1β or (IL-1β + IFN-γ) for 2-20 h showed different kinetics of glucose-stimulated insulin secretion. In iNOS−/− islets, IL-1β at high glucose induced a delayed and prolonged stimulation of insulin secretion, and this was followed by an increase in phospholipase D mRNA expression. After 6 and 24 h, proinsulin convertase 1 and 2 (PC1 and PC2) mRNA expression was suppressed and proinsulin secretion increased from wt islets. In iNOS−/− islets, PC1 expression was recovered after 24 h, and there was no difference in proinsulin secretion. PDX-1 mRNA expression was suppressed independent of NO-formation. We conclude that cytokines induce both NO-dependent and NO-independent functional inhibition of murine β-cells.