INTERLEUKIN-1-BETA INDUCES DIABETES AND FEVER IN NORMAL RATS BY NITRIC-OXIDE VIA INDUCTION OF DIFFERENT NITRIC-OXIDE SYNTHASES

Substantial in vitro evidence suggests that nitric oxide may be a majo r mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibi tion and destruction in the initial events leading to insulin-dependen t diabetes mellitus. Using N-G-nitro-L-arginine methyl ester, an inhib itor of both the constitutive and the cytokine inducible forms of nitr ic oxide synthase, and aminoguanidine, a preferential inhibitor of the inducible form of nitric oxide synthase, we investigated the impact o f inhibiting nitric oxide production on food-intake, body weight and t emperature, blood glucose, plasma insulin, glucagon, corticosterone an d leukocyte- and differential-counts in normal rats injected once dail y for 5 days with interleukin 1 beta (IL-1 beta) (0.8 mu g/rat approxi mate to 4.0 mu g/kg). Inhibition of both the constitutive and the indu cible forms of nitric oxide synthase prevented IL-1 beta-induced fever , hyperglycaemia, hypoinsulinemia, and hyperglucagonemia, and partiall y prevented lymphopenia and neutrophilia, but had no effect on IL-1 be ta-induced anorexia and changes in plasma corticosterone. Preferential inhibition of the inducible form of nitric oxide synthase using two d aily injections of 5 mg/rat of aminoguanidine prevented IL-1 beta-indu ced hyperglycaemia and hypoinsulinaemia, and slightly reduced the pyro genicity of IL-1 on 3 out of 5 days. Higher doses of aminoguanidine (1 00 mg/rat) prevented lymphopenia and neutrophilia. We conclude that ni tric oxide produced by the inducible form of nitric oxide synthase, me diates the IL-1 beta-induced inhibition of insulin release and that th e effect of IL-1 beta on temperature, pancreatic alpha-cells, and leuk ocyte differential counts seems to be mediated by nitric oxide produce d by the constitutive form of nitric oxide synthase.