NICOTINAMIDE PREVENTS INTERLEUKIN-1 EFFECTS ON ACCUMULATED INSULIN RELEASE AND NITRIC-OXIDE PRODUCTION IN RAT ISLETS OF LANGERHANS

Nicotinamide (NA) prevents macrophage- and interleukin-1 (IL-1)-mediat ed beta-cell damage in vitro as well as diabetes development in animal models of insulin-dependent diabetes mellitus (IDDM). IL-1 beta-media ted inhibition of insulin release and damage to beta-cells are associa ted with intracellular production of nitric oxide (NO) radicals. There fore, we studied whether NA prevented IL-1 beta-induced islet NO produ ction, measured as nitrite release from isolated rat islets, and, if s o, whether this action was associated with prevention of IL-1 beta-med iated inhibition of insulin release. NA dose- and time-dependently inh ibited and delayed IL-1 beta-induced islet NO production. Light micros copy detected that 25 mM of NA protected against IL-1 beta-induced isl et damage. Five to 50 mM of NA dose-dependently reduced inhibition of accumulated islet insulin release induced by 150 pg/ml of IL-1 beta. N A was not able to reverse the reduced ability of IL-1 beta-treated isl ets to respond to an acute glucose challenge. NO or nitrite did not in teract directly with NA, because NA did not reduce sodium nitroprussid e-generated nitrite. NO-synthase inhibition with L-arginine depletion abolished NO production but only partially reduced IL-1 beta-induced i nhibition of accumulated insulin release. Complete inhibition of IL-1 beta effects could not be obtained by adding L-arginine analogues to L -arginine-depleted medium, indicating that an NO-independent action of IL-1 beta on islet insulin release may exist. These results suggest a novel mechanism for NA-mediated protection of IL-1-induced beta-cell damage via an inhibitory effect of NA on the formation of NO.