Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta (IL-1 beta) which induces beta -cell apoptosis and exerts inhibitory actions on islet beta -cell insulin secretion. IL-1 beta seems to act chiefly through induction of nitric oxide (NO) synthesis, Hence, IL-1 beta and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect beta -cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca2+ influx through voltage-activated Ca2+ channels (by K+-induced depolarization) was monitored in culture after treatment with IL-1 beta or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1 beta or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with gamma -tocopherol (but not gamma -tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1 beta effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-alpha ]quinoxaline-1-one) or blocking low voltage-activated Ca2+ channels with NiCl2 failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that gamma -tocopherol may partially prevent this, The results suggest that phospholipase C or protein kinase C may be targeted by NO, In contrast, cGMP or low voltage-activated Ca2+ channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the beta -cell, and the protection by gamma -tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process.