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

近年来，有报道称细胞因子在生理和病理条件下具有多种生物活性。至于糖尿病，我们先前已经报道，全身应用TNFpha和TNFbeta可显著抑制NOD小鼠的胰岛素依赖型糖尿病(IDDM)的发展，尽管这两种药物被认为在胰岛素炎性病变中起致病作用。在这项研究中，我们进一步证明了细胞因子不仅在IDDM中，而且在非胰岛素依赖型糖尿病(NIDDM)和糖尿病并发症中也发挥了不同的作用。系统地给予重组人TNFβ完全阻止了NOD小鼠IDDM的发生。这种抑制作用是由于在自身免疫的不同阶段，如诱导期和效应期对抗胰岛效应细胞的抑制。链球菌制剂(OK-432)、卡介苗(BCG)和完全弗氏佐剂(CFA)等细胞因子诱导剂显著改善了NIDDM动物模型的糖耐量。在体内，糖尿病动物在长期高血糖状态下，肿瘤坏死因子α的产生显著增加，提示肿瘤坏死因子α可能与糖尿病并发症有关。我们发现糖尿病患者血清中肿瘤坏死因子α水平升高，N-乙酰半胱氨酸抑制肿瘤坏死因子α的产生显著抑制了链脲佐菌素诱导的糖尿病大鼠糖尿病周围神经病变的发展。已知的肿瘤坏死因子α抑制剂己酮可可碱对神经病变也有类似的有益作用。因此，本研究展示了细胞因子在糖尿病及其并发症中的各种可取和不可取的作用以及细胞因子控制的治疗应用。

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.