THE EFFECT OF NITRIC-OXIDE DONORS ON INSULIN-SECRETION, CYCLIC-GMP AND CYCLIC-AMP IN RAT ISLETS OF LANGERHANS AND THE INSULIN-SECRETING CELL-LINES HIT-T15 AND RINM5F

The aim of this study was to investigate whether short-term treatment with nitric oxide donors could mimic cytokine inhibition of insulin se cretion. We tested the nitric oxide generating compounds 3-morpholinos ydnonimine (SIN-1), S-nitroso-N-penicillamine (SNAP), S-nitrosoglutath ione and hydroxylamine for their ability to inhibit insulin secretion, raise cyclic GMP and lower cyclic AMP levels in isolated rat islets o f Langerhans and the insulin-secreting cell lines HIT-T15 and RINm5F. In islets, all nitric olcide donors inhibited glucose-induced insulin secretion and raised cyclic GMP levels. SIN-1 and S-nitrosoglutathione also reduced cyclic AMP, while SNAP and hydroxylamine had no effect. Insulin secretion in HIT-T15 cells was inhibited by SIN-1, SNAP and hy droxylamine and in RINm5F cells by hydroxylamine. Inhibition of HIT-T1 5 and RINm5F cell insulin secretion was not accompanied by an increase in cyclic GMP levels. The degree of inhibition of insulin secretion w as unrelated to the extent of release of nitric oxide by the compounds as measured by nitrite and nitrate production. More effective inhibit ion by S-nitrosoglutathione and hydroxylamine versus SIN-1 and SNAP ma y be related to intracellular versus extracellular site of nitric oxid e generation.