Nicotinamide Prevents Interleukin-1 Effects on Accumulated Insulin Release and Nitric Oxide Production in Rat Islets of Langerhans

Abstract

Nicotinamide (NA) prevents macrophage- and interleukin-1 (IL-1)-mediated β-cell damage in vitro as well as diabetes development in animal models of insulin-dependent diabetes mellitus (IDDM). IL-1 β-mediated inhibition of insulin release and damage to β-cells are associated with intracellular production of nitric oxide (NO) radicals. Therefore, we studied whether NA prevented IL-1 β-induced islet NO production, measured as nitrite release from isolated rat islets, and, if so, whether this action was associated with prevention of IL-1 β-mediated inhibition of insulin release. NA dose- and time-dependently inhibited and delayed IL-1 β-induced islet NO production. Light microscopy detected that 25 mM of NA protected against IL-1 β-induced islet damage. Five to 50 mM of NA dose-dependently reduced inhibition of accumulated islet insulin release induced by 150 pg/ml of IL-1 β. NA was not able to reverse the reduced ability of IL-1 β-treated islets to respond to an acute glucose challenge. NO or nitrite did not interact directly with NA, because NA did not reduce sodium nitroprusside-generated nitrite. No-synthase inhibition with L-arginine depletion abolished NO production but only partially reduced IL-1 β-induced inhibition of accumulated insulin release. Complete inhibition of IL-1 β effects could not be obtained by adding L-arginine analogues to L-arginine-depleted medium, indicating that an NO-independent action of IL-1 β on islet insulin release may exist. These results suggest a novel mechanism for NA-mediated protection of IL-1–induced P-cell damage via an inhibitory effect of NA on the formation of NO.