吡格列酮改善胰岛素抵抗状态下氧化应激水平及分子机制探讨

中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (3): 245-249.

吡格列酮改善胰岛素抵抗状态下氧化应激水平及分子机制探讨

李兰芳^1,2, 黄秀清², 原慧萍², 李淼², 王抒², 满永², 黎健²

¹北京协和医学院研究生院, 北京100730;
²卫生部北京医院老年医学研究所/卫生部老年医学重点实验室, 北京100730

收稿日期:2009-02-12 修回日期:2009-02-12 发布日期:2020-10-27
作者简介:李兰芳, 女, 博士研究生, 主要从事2 型糖尿病的分子机制研究。Tel:13264130629 E-mail:wjliu829 @yahoo.com.cn
基金资助:
国家重点基础研究发展规划项目(973 计划) (2006CB503910); 国家自然科学基金(30572082)

Approach of the molecular mechanisms and the oxidative stress levels on pioglitazone improving insulin resistance condition

LI Lan-fang^1,2, HUANG Xiu-qing², YUAN Hui-ping², LI Miao², WANG Shu², MAN Yong², LIJian²

¹Graduate School of Peking Union Medical College, Beijing 100730, China;
²Beijing Institute of Geriatrics, Beijing Hospital, Key Laboratory of Geriatrics, Ministry of Health, Beijing 100730, China

Received:2009-02-12 Revised:2009-02-12 Published:2020-10-27

摘要/Abstract

摘要： 目的探讨吡格列酮(Pio) 对胰岛素抵抗状态下的氧化应激水平的影响, 并初步探讨Pio 改善胰岛素抵抗作用的分子机制。方法用TNF-α(4 ng mL) 刺激人肝癌细胞HepG2, 建立胰岛素抵抗细胞模型。MTT 法观察细胞毒性作用;氧化酶法检测细胞培养液中的葡萄糖浓度;用DCFH-DA荧光探针标记, 流式细胞仪检测细胞内活性氧(ROS) 的水平;Western blotting 检测氨基末端激酶(JNK) 、磷酸化氨基末端激酶(p-JNK) 和胰岛素受体底物1(IRS1) 的表达。结果 TNF-α刺激HepG2后, 导致葡萄糖摄取障碍, 细胞培养液上清中葡萄糖浓度显著升高, 细胞内ROS 的水平显著升高,JNK 被激活, IRS1 的表达降低。Pio 可显著降低ROS 的水平, 抑制JNK 的磷酸化, 促进IRS1 的表达, 改善胰岛素抵抗。结论 Pio 通过降低氧化应激水平, 抑制JNK 信号通路, 改善胰岛素抵抗状态。

关键词: 胰岛素抵抗, 氧化应激, TNF-α

Abstract: AIM: To investigate the effects of pioglitazone on oxidative stress levels and insulin resistance and initially approach the molecular mechanisms of pioglitazone improving insulin resistance. METHODS: The insulin resistance cell models were induced by TNF-α(4 ng mL) to stimulate human hepatoma carcinoma cell HepG2.The cytotoxicity of HepG2 was observed by MTT.The concentrations of glucose in cell culture fluid of HepG2 were detected using a glucose oxidase assay kit.The levels of intracellular reactive oxygen species were detected by DCFH-DA fluorescent probe and flow cytometry.The expressions of JNK, p-JNK, IRS1 were measured by Western blotting. RESULTS: After HepG2 was stimulated by TNF-α, the glucose uptake was blocked, the glucose concentrations were significantly increased in cell culture fluid, the active oxygen levels were significantly increased in cells, the JNK was activated, the expression of IRS1 was decreased.Pioglitazone could significantly decrease the active oxygen levels, inhibit JNK phosphorylation, promote the expression of IRS1, improve insulin resistance. CONCLUSION: Pioglitazone could improve the insulin resistance condition by degrading oxidative stress levels and inhibiting JNK passway.

Key words: insulin resistance, oxidative stress, TNF-α

中图分类号:

R587

李兰芳, 黄秀清, 原慧萍, 李淼, 王抒, 满永, 黎健. 吡格列酮改善胰岛素抵抗状态下氧化应激水平及分子机制探讨[J]. 中国临床药理学与治疗学, 2009, 14(3): 245-249.

LI Lan-fang, HUANG Xiu-qing, YUAN Hui-ping, LI Miao, WANG Shu, MAN Yong, LIJian. Approach of the molecular mechanisms and the oxidative stress levels on pioglitazone improving insulin resistance condition[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(3): 245-249.

参考文献

[1] Evans JL, Goldfine ID, Maddux BA, et al.Oxidative stress and stress-activated signaling pathways:A unifying hypothesis of type 2 diabetes[J].Endocr Rev, 2002, 23(5):599-622.
[2] Houstis N, Rosen ED, Lander ES.Reactive oxygen species have a causal role in multiple forms of insulin resistance[J].Nature, 2006, 440(7086):944-948.
[3] Song F, Jia W, Yao Y, et al.Oxidative stress, antioxidant status and DNA damage in patients with impaired glucose regulation and newly diagnosed type 2 diabetes[J].Clin Sci (Lond), 2007, 112(12):599-606.
[4] Kaneto H, Katakami N, Kawamori D, et al.Involvement of oxidative stress in the pathogenesis of diabetes[J].Antioxid Redox Signal, 2007, 9(3):355-366.
[5] Semple RK, Chatterjee VK, O'Rahilly S.PPAR gamma and human metabolic disease[J].J Clin Invest, 2006, 116(3):581-589.
[6] Li G, Barrett EJ, BarrettMO, et al.Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway[J].Endocrinology, 2007, 148(7):3356-3363.
[7] Meigs JB, Larson MG, Fox CS, et al.Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study[J].Diabetes Care, 2007, 30(10):2529-2535.
[8] Wilson C, Vereshchagina N, Reynolds B, et al.Extracellular and subcellular regulation of the PI3K Akt cassette: new mechanisms for controlling insulin and growth factor signalling[J].Biochem Soc Trans, 2007, 35(2):219-221.
[9] Honjo S, Yokote K, Fujishiro T, et al.Early amelioration of insulin resistance and reduction of interleukin-6 in Werner syndrome using pioglitazone[J].J Am Geriatr Soc, 2008, 56(1):173-174.
[10] Teramoto T, Yamada N, Shirai K, et al.Effects of pioglitazone hydrochloride on Japanese patients with type 2 diabetes mellitus[J].J Atheroscler Thromb, 2007, 14(2):86-93.

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