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

糖尿病和糖尿病并发症中细胞因子的异常表达及其细胞因子控制的治疗

• 批准号: 06670997
• 负责人: SATOH Jo
• 金额: $ 1.54万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670997/
• 关键词: TNFalpha; TNFbeta; NOD mouse; KK-Ag mouse; IDDM; NIDDM; N-acetylcysteine; diabetic neuropathy; TNF_α; TNF_β; インスリン抵抗性; 糖尿病; 糖尿病性合併症; サイトカイン; N-アセチルシスティン; IL-1

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.

近年来研究发现，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，我们之前报道过NOD小鼠胰岛素依赖型糖尿病（IDDM）的发展被全身给药tnffalpha和TNFbeta显著抑制，尽管它们在胰岛素病变中起致病作用。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）和糖尿病并发症中的各种作用。全身给药重组人tnf - β完全阻止NOD小鼠IDDM的发展。tnf - β的这种抑制作用是由于在自身免疫的各个阶段（如诱导期和效应期）抑制抗胰岛效应细胞。细胞因子诱导剂如链球菌制剂（OK-432）、卡介苗和完全弗氏佐剂（CFA）可显著改善NIDDM动物模型的葡萄糖耐量。在长期高血糖状态下，糖尿病动物体内TNFalpha的产生显著增加，表明TNFalpha可能与糖尿病并发症有关。我们发现糖尿病患者血清TNFalpha水平升高，用n-乙酰半胱氨酸抑制TNFalpha的产生可显著抑制链脲霉素诱导的糖尿病大鼠糖尿病周围神经病变的发展。己酮茶碱，一种已知的TNFalpha抑制剂，对神经病变也有类似的有益作用。因此，本研究显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。

项目成果

M. Sagara, et al.: "Inhibition with N-acetylcysteine of development of peripheral neuropathy in streptozotocin-induced diabetic rats" Diabetologia. (in press). (1996)

M. Sagara 等人：“用 N-乙酰半胱氨酸抑制链脲佐菌素诱导的糖尿病大鼠周围神经病变的发展”Diabetologia。

K. Takahashi, et et.: "Analysis of mechanism of action of lymphotoxin on prevention of cyclophospnamide-induced diabetes in NOD mice" Journal of Autoimmunity. 8. 335-346 (1995)

K. Takahashi 等人：“淋巴毒素预防 NOD 小鼠环磷酰胺诱发糖尿病的作用机制分析”《自身免疫杂志》。

Sagara M,Satoh J,Wada R,Yagihashi S,Takahashi K,Fukuzawa M,Muto G,Muto Y,Toyota T: "Inhibition with Nacetylcysteine of development of peripheralneuropathy in streptozotocin-induced diabetic rats." Diabetologia. (in press). (1996)

Sagara M、Satoh J、Wada R、Yagihashi S、Takahashi K、Fukuzawa M、Muto G、Muto Y、Toyota T：“用 N 乙酰半胱氨酸抑制链脲佐菌素诱导的糖尿病大鼠周围神经病变的发展。”

K, Takahashi: "Reduced expression of c-Fos in female NOD mouse thymocytes and up-regulation with human lymphotoxin" Cellular Immunology. 164. 287-294 (1995)

K，Takahashi：“雌性 NOD 小鼠胸腺细胞中 c-Fos 的表达减少，人淋巴毒素上调”细胞免疫学。

Mikio Sagara: "Inhibition with N-acetylcysteine of enhanced production of tumcr necrosis factor in streptozotocin-induced diabetic rats." Clin Immunl Immunopathol. 70. 333-337 (1994)

Mikio Sagara：“用 N-乙酰半胱氨酸抑制链脲佐菌素诱导的糖尿病大鼠中肿瘤坏死因子的增加。”