Interleukin-1β-induced nitric oxide production from isolated rat islets is modulated by D-glucose and 3-isobutyl-1-methyl xanthine

Abstract

Andersen HU, Mauricio D, Karlsen AE, Mandrup-Poulsen T, Nielsen JH, Nerup J. Interleukin-nitric oxide production from isolated rat islets is modulated by d-glucose and 3-isobutyl-1-methyl xanthine. Eur J Endocrinol 1996:134:251–9. ISSN 0804–4643 Interleukin-1β has been proposed to cause selective β-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1β is modulated by the concentration of d-glucose in the medium. The aim of this study was to investigate if d-glucose-mediated modulation of interleukin-1β effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1β-induced nitrite production. We demonstrated that d-glucose potentiated interleukin-1β-induced nitrite production in rat islets without affecting the mRNA level of the inducible nitric oxide synthase. This effect was dissociated from interleukin-1β action on insulin release, since a relative protection against interleukin-1β effects on acute insulin release was found at high (28 mmol/l) concentrations of d-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action of interleukin-1β Neither l-glucose nor the secretagogues l-leucine, tolbutamide and β-isobutyl-1-methyl xanthine shared the potentiating effect of d-glucose, The phosphodiesterase inhibitor β-isobutyl-1-methyl xanthine reduced interleukin-1β-induced nitrite production at 3.3 mmol/l d-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-1-methyl xanthine resulted in a threefold reduction in the mRNA level of interleukin-1β-induced inducible nitric oxide synthase. We conclude that interleukin-1β-induced islet nitric oxide synthesis is augmented by d-glucose but not by non-substrate secretagogues, and that secretagogues that elevate cAMP inhibit islet nitric oxide production. Jørn Nerup, Steno Diabetes Center, Niels Steensens vej 2, DK-2820 Gentofte, Denmark