Cytokine regulation of pancreatic -cell function with special reference to the pathogenesis of type 1 diabetes

Abstract: Cytokines produced by inflammatory cells have been implicated in the pathogenesis of type 1 diabetes. The overall aim of the present work was to test how different cytokines, supposed to be present in the insulitic lesion, could influence the function of islets of Langerhans. Moreover, it was studied if inhibitors of certain cellular functions (iNOS enzyme and the proteasome) could reverse cytokine induced suppression of islet function as well as diabetes development in an animal model.The cytokine IL-4 had a slight suppressive effect on rat pancreatic islets by itself, and apotentiating effect on IL-1β induced inhibition of (pro)insulin biosynthesis. These effects seemed to be unrelated to nitric oxide (NO) formation. The cytokine IL-13 had no effect of itsown on pancreatic islet function, but could counteract IL-1β induced inhibition of glucose oxidation. When IL-4 + IL-13 were present together no protective effect was found.IFN-γ and TNF-α + LFN-γ induced a decrease in medium insulin accumulation and basal insulin secretion, while glucose-stimulated insulin release was increased or unaffected. The cytokines combined induced NO formation while this parameter was unaffected by the cytokines alone. This suggests that the effects of IFN- g alone are NO-independent. The iNOS inhibitor S-methyl-thiocitrulline dose-dependently decreased NO formation induced by IL-1β and counteracted the suppression of islet function induced by the cytokine, but did not prevent insulitis or type 1 diabetes in mice injected with multiple low doses of streptozotocin.IL-12 had minor suppressive effects on islets from normal rats and mice, effects that wereunrelated to NO formation. Functionally suppressed β-cells isolated from NOD mice up to 26 weeks of age recovered after 7 days in culture. Culture with IL-2 + IL-12 could interfere withthis recovery in islets from 12 week old NOD mice. Inhibition of the proteasome, using MG115, blocked NO formation inducedby IL-1β probably via inhibition of NF-κB. This correlated to protection from suppressed glucose oxidation. IL-1β also increased expression of the inducible proteasome subunit LMP7.In conclusion, cytokines can have both stimulatory and inhibitory effects on islet function and some of these effects seem to be unrelated to NO formation. Also, the proteasome system appears to be involved in cytokine induced inhibition of islet function.