INTERLEUKIN-1-BETA-INDUCED NITRIC-OXIDE PRODUCTION FROM ISOLATED RAT ISLETS IS MODULATED BY D-GLUCOSE AND 3-ISOBUTYL-1-METHYL XANTHINE

Interleukin-1 beta has been proposed to cause selective beta-cell dest ruction via the induction of nitric oxide synthesis. The cytotoxic eff ect of interleukin-1 beta is modulated by the concentration of D-gluco se in the medium. The aim of this study was to investigate if D-glucos e-mediated modulation of interleukin-1 beta effects on insulin release from isolated rat islets was related to modulation of nitric oxide pr oduction. Further, we wished to investigate the effects of agents incr easing the intracellular concentration of cAMP on interleukin-1 beta-i nduced nitrite production, We demonstrated that D-glucose potentiated interleukin-1 beta-induced nitrite production in rat islets without af fecting the mRNA level of the inducible nitric oxide synthase. This ef fect was dissociated from interleukin-1 beta action on insulin release , since a relative protection against interleukin-1 beta effects on ac ute insulin release was found at high (28 mmol/l) concentrations of D- glucose, and blocking nitrite production by the L-arginine analog amin oguanidine, which selectively inhibits the cytokine-inducible nitric o xide synthase, did not result in protection against the inhibitory act ion of interleukin-1 beta. Neither L-glucose nor the secretagogues L-l eucine, tolbutamide and 3-isobutyl-1-methyl xanthine shared the potent iating effect of D-glucose. The phosphodiesterase inhibitor 3-isobutyl -l-methyl xanthine reduced interleukin-1 beta-induced nitrite producti on at 3.3 mmol/l D-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-l-methyl xanthine r esulted in a threefold reduction in the mRNA level of interleukin-1 be ta-induced inducible nitric oxide synthase. We conclude that interleuk in-1 beta-induced islet nitric oxide synthesis is augmented by D-gluco se, but not by non-substrate secretagogues, and that secretagogues tha t elevate cAMP inhibit islet nitric oxide production.