Abnomal cytokine expression in diabetes mellitus and diabetic complications, and their treatment by cytokine control

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Recently it has been reported that cytokines have a variety of bioactivities in physiological and pathological conditions. As to diabetes mellitus, we have previously reported that development of insulin-dependent diabetes mellitus (IDDM) in NOD mice is significantly inhibited by systemic administration of TNFalpha and TNFbeta, although these are implicated to play pathogenic roles in insulitis lesions. In this study we have further shown various roles of cytokines not only in IDDM but also in non-insulin dependent diabetes mellitus (NIDDM) and diabetic complications.Systemic administration of recombinant human TNFbeta completely prevented development of IDDM in NOD mice. This suppressive effect of TNFbeta was due to inhibition of anti-islet effector cells in various phases in autoimmunity, e. g., induction and effector phase. Cytokine inducers such as streptococcal preparation (OK-432), BCG and complete Freund's adjuvant (CFA) remarkably improved glucose tolerance in NIDDM animal models. In vivo TNFalpha production was significantly increased in long term hyperglycemic condition in diabetic animals, indicating that TNFalpha might be related to diabetic complications. We found the increased serum levels of TNFalpha in diabetic patients, and that suppression of TNFalpha production with N-acetylcysteine significantly inhibited development of diabetic peripheral neuropathy in streptozotocin-induced diabetic rats. Pentoxifylline, a known TNFalpha inhibitor, had similar beneficial effect on the neuropathy.Thus, a variety of desirable and undesirable role of cytokines in diabetes and its complications and therapeutic application of cytokine control has been shown in this study.