Aims/hypothesis: Pro-inflammatory cytokines cause beta cell secretory dysfunction and apoptosis-a process implicated in the pathogenesis of type 1 diabetes. Cytokines induce the expression of inducible nitric oxide (NO) synthase (iNOS) leading to NO production. NO contributes to cytokine-induced apoptosis, but the underlying mechanisms are unclear. The aim of this study was to investigate whether NO modulates signalling via mitogenactivated protein kinases (MAPKs) and Akt. Materials and methods: MAPK activities in INS-1 cells and isolated islets were determined by immunoblotting and in vitro kinase assay. Apoptosis was determined by ELISA measurement of histone-DNA complexes present in cytoplasm. Results: Apoptosis in INS-1 cells induced by IL-1β plus IFNγ was dependent on NO production as demonstrated by the use of the NOS blocker N G -methyl-Larginine. Accordingly, an NO donor (S-nitroso-N-acetyl-D, L-penicillamine, SNAP) dose-dependently caused apoptosis in INS-1 cells. SNAP activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but suppressed the activity of extracellular signal-regulated kinase MAPK. In rat islets, NOS inhibition decreased JNK and p38 activities induced by a 6-h exposure to IL-1β. Likewise, IL-1β-induced JNK and p38 activities were lower in iNOS (−/−) mouse islets than in wild-type islets. In human islets, SNAP potentiated IL-1β-induced JNK activation. The constitutive level of active, Ser473-phosphorylated Akt in INS-1 cells was suppressed by SNAP. IGF-I activated Akt and protected against SNAP-induced apoptosis. The anti-apoptotic effect of IGF-I was not associated with reduced JNK activation. Conclusions/interpretation: We suggest that NO contributes to cytokine-induced apoptosis via potentiation of JNK activity and suppression of Akt.