Insulin resistance is a cellular antioxidant defense mechanism

Kyle L. Hoehn, Adam B. Salmon, Cordula Hohnen-Behrens, Nigel Turner, Andrew J. Hoy, Ghassan J. Maghzal, Roland Stocker, Holly Van Remmen, Edward W. Kraegen, Greg J. Cooney, Arlan R. Richardson, David E. James

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314 Scopus citations

Abstract

We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.

Original languageEnglish (US)
Pages (from-to)17787-17792
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number42
DOIs
StatePublished - Oct 20 2009

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Keywords

  • Diabetes
  • Mitochondria
  • Superoxide

ASJC Scopus subject areas

  • General

Cite this

Hoehn, K. L., Salmon, A. B., Hohnen-Behrens, C., Turner, N., Hoy, A. J., Maghzal, G. J., Stocker, R., Van Remmen, H., Kraegen, E. W., Cooney, G. J., Richardson, A. R., & James, D. E. (2009). Insulin resistance is a cellular antioxidant defense mechanism. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17787-17792. https://doi.org/10.1073/pnas.0902380106