Reactive oxygen species have a causal role in multiple forms of insulin resistance
Reactive oxygen species have a causal role in multiple forms of insulin resistance
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DOI：
10.1038/nature04634
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发表时间：
2006-04-13
期刊：
影响因子：
64.8
通讯作者：
Lander, ES
中科院分区：
文献类型：
--
作者：
Houstis, N;Rosen, ED;Lander, ES
胰岛素抵抗是2型糖尿病的主要特征，也是其他临床和实验设置的广泛特征。为什么胰岛素抵抗会在如此多的情况下发生，我们知之甚少。触发胰岛素抵抗的各种侮辱是否通过一个共同的机制起作用?或者，正如已经提出的(1)，它们是否使用不同的细胞途径？在这里，我们报告了对胰岛素抵抗的两种细胞模型的基因组分析，一种是由细胞因子肿瘤坏死因子- α诱导的，另一种是由糖皮质激素地塞米松诱导的。基因表达分析表明，两种模型中的活性氧（ROS）水平都有所增加，我们通过测量细胞氧化还原状态证实了这一点。以前曾有人提出活性氧与胰岛素抵抗有关，尽管其因果关系的证据不足。我们在细胞培养中测试了这一假设，使用了六种旨在改变ROS水平的处理方法，包括两种小分子和四种转基因；它们都不同程度地改善了胰岛素抵抗。其中一种治疗方法在肥胖、胰岛素抵抗的老鼠身上进行了测试，结果显示可以改善胰岛素敏感性和葡萄糖稳态。总之，我们的研究结果表明，在许多情况下，ROS水平升高是胰岛素抵抗的重要触发因素。
Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested(1), do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-alpha and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.