肿瘤坏死因子-α在体内诱导的胰岛素抵抗及其被曲格列酮预防的情况。

TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone.

作者信息

Miles P D, Romeo O M, Higo K, Cohen A, Rafaat K, Olefsky J M

机构信息

Department of Surgery, University of California, San Diego 92103, USA.

出版信息

Diabetes. 1997 Nov;46(11):1678-83. doi: 10.2337/diab.46.11.1678.

DOI:10.2337/diab.46.11.1678

PMID:9356012

Abstract

Tumor necrosis factor (TNF)-alpha may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of TNF-alpha-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rats were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After approximately 10 days, rats were infused with TNF-alpha for 4-5 days, producing a plasma concentration of 632 +/- 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a submaximal (24 micromol x kg[-1] x min[-1]) and maximal insulin infusion rate (240 micromol x kg[-1] x min[-1]). TNF-alpha infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 +/- 10 vs. 141 +/- 4 micromol x kg[-1] x min[-1], P < 0.05), maximal GDR (175 +/- 8 vs. 267 +/- 6 micromol x kg[-1] x min[-1], P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 +/- 39 vs. 406 +/- 32 fmol ATP/fmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 +/- 24 vs. 48 +/- 6 micromol/l, P < 0.05) and free fatty acid (FFA) concentration (2.56 +/- 0.76 vs. 0.87 +/- 0.13 mmol/l, P < 0.01). Troglitazone treatment completely prevented the TNF-alpha-induced decline in submaximal GDR (133 +/- 16 vs. 141 +/- 4 micromol x kg[-1] x min[-1], NS) and maximal GDR (271 +/- 19 vs. 267 +/- 6 micromol x kg[-1] x min[-1], NS). The hyperlipidemia was partially corrected by troglitazone (1.53 +/- 0.28 vs. 0.87 +/- 0.13 mmol/l, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug. Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-alpha plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove useful in its treatment.

摘要

肿瘤坏死因子（TNF）-α可能在肥胖和非胰岛素依赖型糖尿病（NIDDM）的胰岛素抵抗中起作用。曲格列酮是一种新型口服活性降糖药，已证实在糖尿病动物模型和NIDDM患者中，它能改善胰岛素抵抗和高胰岛素血症。为了确定该药物是否能预防TNF-α诱导的胰岛素抵抗的发生，对输注细胞因子并预先用曲格列酮处理的大鼠的葡萄糖代谢情况进行了评估。正常雄性斯普拉格-道利大鼠喂食添加或不添加曲格列酮（0.2%作为食物添加剂）的普通粉状食物。大约10天后，大鼠输注TNF-α 4 - 5天，使血浆浓度达到632±30 pg/ml。采用正常血糖-高胰岛素钳夹技术，在次最大（24 μmol·kg⁻¹·min⁻¹）和最大胰岛素输注速率（240 μmol·kg⁻¹·min⁻¹）下测量体内胰岛素作用。输注TNF-α导致次最大胰岛素刺激的葡萄糖处置率（GDR）显著降低（97±10对141±4 μmol·kg⁻¹·min⁻¹，P<0.05）、最大GDR降低（175±8对267±6 μmol·kg⁻¹·min⁻¹，P<0.01）以及胰岛素受体酪氨酸激酶活性（IR-TKA）降低（248±39对406±32 fmol ATP/fmol IR，P<0.05）。它还导致基础胰岛素（90±24对48±6 μmol/L，P<0.05）和游离脂肪酸（FFA）浓度显著升高（2.56±0.76对0.87±0.13 mmol/L，P<0.01）。曲格列酮治疗完全预防了TNF-α诱导的次最大GDR下降（133±16对141±4 μmol·kg⁻¹·min⁻¹，无显著差异）和最大GDR下降（271±19对267±6 μmol·kg⁻¹·min⁻¹，无显著差异）。曲格列酮部分纠正了高脂血症（1.53±0.28对0.87±0.13 mmol/L，P<0.05），而IR-TKA和胰岛素浓度不受该药物影响。曲格列酮可能通过降低血液中的FFA浓度和/或通过在肌肉中胰岛素受体自身磷酸化远端的细胞内位点刺激葡萄糖摄取来恢复胰岛素作用。如果TNF-α在肥胖/NIDDM综合征的发生中起作用，曲格列酮可能在其治疗中被证明是有用的。