DOES NITRIC-OXIDE MEDIATE AUTOIMMUNE DESTRUCTION OF BETA-CELLS - POSSIBLE THERAPEUTIC INTERVENTIONS IN IDDM

Cytokines have been implicated as immunological offector molecules that induce dysfunction and destruction of the pancreatic-beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1-beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects IL-1-beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic Complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce antidiabetogenic effects in the NOD mouse. This antidiabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction. The role of nitric oxide in both cytokine-mediated beta-cell dysfunction, and the antidiabetogenic effects of cytokines, as well as the potential therapeutic use of aminoguanidine, are evaluated in this study.