Houstis Nicholas, Rosen Evan D, Lander Eric S
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.
Nature. 2006 Apr 13;440(7086):944-8. doi: 10.1038/nature04634.
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, 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.
胰岛素抵抗是2型糖尿病的主要特征，也是许多其他临床和实验环境的特征。对于胰岛素抵抗为何在如此多的情况下发生，人们知之甚少。引发胰岛素抵抗的各种损伤是通过共同机制起作用吗？或者，如有人所提出的，它们使用不同的细胞途径？在此，我们报告了对两种胰岛素抵抗细胞模型的基因组分析，一种由细胞因子肿瘤坏死因子-α处理诱导，另一种由糖皮质激素地塞米松诱导。基因表达分析表明，两种模型中的活性氧（ROS）水平均升高，我们通过细胞氧化还原状态的测量证实了这一点。此前有人提出ROS参与胰岛素抵抗，尽管因果关系的证据很少。我们在细胞培养中使用六种旨在改变ROS水平的处理方法（包括两种小分子和四种转基因）对这一假设进行了测试；所有这些处理都不同程度地改善了胰岛素抵抗。其中一种处理方法在肥胖、胰岛素抵抗小鼠中进行了测试，结果显示可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，ROS水平升高是许多情况下胰岛素抵抗的重要触发因素。
