Nitric oxide production in islets from nonobese diabetic mice: Aminoguanidine-sensitive and -resistant stages in the immunological diabetic process

The role of nitric oxide (NO^•) in the development of immunologically induced diabetes was examined. Transfer of spleen cells obtained from diabetic female nonobese diabetic (NOD) mice to nondiabetic irradiated males induced diabetes 11-13 days after transfer. Islets isolated from recipient male mice produced NO^• in a time-dependent fashion. The production of nitrite was initially detected at day 6 after transfer, with increasing levels by days 9 and 13. Under similar conditions glucose-induced insulin secretion by isolated NOD mouse islets was irreversibly reduced by ≈40% at days 6, 9, and 13 after transfer of spleen cells. The number of islets harvested per pancreas by the 9th and 13th day after transfer was decreased by 20-25% as compared to controls. Treatment of male NOD mice with aminoguanidine, an inhibitor of the inducible form of NO^• synthase, reduced the production of NO^• in islets and delayed the development of diabetes by 3-8 days. The temporary inhibition by aminoguanidine was dependent on both inhibitor concentration and number of spleen cells transferred. These results indicate that NO^• is produced in NOD islets as a result of an immunological diabetogenic process and suggests a role of this compound in the immunological diabetic process.