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Reactive oxygen species have a causal role in multiple forms of insulin resistance

Abstract

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 suggested1, 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-α 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.

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Figure 1: Characterization of the insulin-resistant state.
Figure 2: Effect of antioxidants on insulin resistance.
Figure 3: Effect of transgenes on insulin resistance.
Figure 4: Effects of chronic treatment with MnTBAP or rosiglitazone on obese mice.

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Acknowledgements

We thank J. Zabolotny for assistance with signal transduction assays. We also thank D. Altshuler, O. Peroni and members of the Rosen and Lander laboratories for discussions. This work was supported in part by grants from the NIH (to E.D.R. and E.S.L.), the Hertz Foundation (N.H.) and the Broad Institute of MIT and Harvard. Author Contributions E.D.R. and E.S.L. co-directed this work.

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Correspondence to Evan D. Rosen or Eric S. Lander.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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This file contains full methods, Supplementary References, Supplementary Tables 1–4 and legends for Supplementary Figures 1–3. (PDF 83 kb)

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This file contains Supplementary Figures 1–3. (PDF 256 kb)

Supplementary Notes

This file contains the MIAME Checklist for array based CGH experiments. (DOC 63 kb)

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Houstis, N., Rosen, E. & Lander, E. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 (2006). https://doi.org/10.1038/nature04634

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