Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase
Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase
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DOI：
10.1073/pnas.0308096101
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发表时间：
2004-06-15
影响因子：
11.1
通讯作者：
Lei, XG
中科院分区：
文献类型：
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作者：
McClung, JP;Roneker, CA;Lei, XG
胰岛素抵抗是2型糖尿病的标志，与氧化应激有关。然而，活性氧或特定的抗氧化酶在其发展中的作用尚未在生理条件下进行测试。我们的研究目的是探讨谷胱甘肽过氧化物酶1（GPX 1），细胞内硒蛋白，减少过氧化氢（H2 O2）在体内，对葡萄糖代谢和胰岛素功能的过度表达的影响。GPX 1过表达（OE）和WT雄性小鼠（n = 80）从8至24周龄喂食硒充足的饮食（0.4 mg/kg）。与WT相比，OE小鼠在24周龄时出现（P < 0.05）高血糖症（117对149 mg/dl）、高胰岛素血症（419对1,350 pg/ml）和升高的血浆瘦素（5对16 ng/ml）。同时，这些小鼠比WT小鼠更重（37对27 g，P < 0.001）和更胖（37%对17%脂肪，P < 0.01）。在胰岛素激发后30-60分钟，OE小鼠的血糖降低比WT小鼠少25%（P < 0.05）。其胰岛素抵抗与胰岛素刺激的肝脏胰岛素受体（β亚基）和肝脏及比目鱼肌Akt（Ser（473）和Thr（308））磷酸化降低30-70%（P < 0.05）有关。在这里，我们报告的发展，胰岛素抵抗的哺乳动物与抗氧化酶的表达升高，并建议GPX 1活性增加可能会干扰胰岛素功能，通过过度淬灭细胞内的活性氧所需的胰岛素敏化。
Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H2O2) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.