ANTIDIABETIC EFFECTS OF INOSINE

Inflammatory islet cell injury in new-onset Type 1 diabetes is a form of autoimmune tissue injury that may be "switched" from the malignant state responsible for islet damage to a benign condition where little or no beta-cell damage occurs. This latter process involves appropriate stimulation of the immune system and is mediated by the development of an immune response that is likely to take weeks or possibly months to be completely effective. What is required is a therapeutic intervention that will control acute islet damage during the time needed for the adjustment of the malignant immune response during the "honeymoon" phase of the disease. We now present new data which suggest that there may be a strategy that could both arrest islet damage during the honeymoon phase, and which could also be used to prevent recurrent disease when islets are transplanted to diabetic individuals. This strategy involves the use of the anti-inflammatory purine, inosine, to arrest ongoing inflammatory islet beta-cell damage, while the autoimmune response is being converted from the malignant to the benign state. Our recent data have demonstrated that unexpectedly, the non-toxic purine inosine exerts multiple anti-inflammatory and immunomodulatory effects. Inosine suppresses the production of pro-inflammatory cytokines implicated in islet-cell injury, including TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1-alpha, and IFN-gamma. Further, inosine enhanced the production of the anti-inflammatory cytokine IL-10. Enteral administration of inosine to streptozotocin-diabetic rats markedly delays the development of diabetes and reduces the proportion of animals that develop diabetes. These effects are associated with a significant preservation of pancreatic insulin content and a beneficial modulation of intraislet cytokine production. In the current application, we propose further studies, using the NOD model of diabetes, to establish the efficacy of inosine in suppressing diabetes development and to establish the therapeutic window of intervention. Given that inosine is an approved over-the-counter nutritional supplement and has an excellent record of safety in man, we envision an accelerated path of preclinical and clinical development, if inosine confirms to be effective in the NOD model.