Editors' ChoiceMetabolism

Redox-Regulated Insulin Resistance

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Science's STKE  18 Apr 2006:
Vol. 2006, Issue 331, pp. tw126
DOI: 10.1126/stke.3312006tw126

Resistance to signaling by the hormone insulin is a major problem, not only in patients with type 2 diabetes but also in a broad range of other physiological states, including pregnancy, obesity, and septic shock. Houstis et al. wondered how these varied conditions might all produce a common effect on insulin signaling and whether there might be a common pathway by which they impact cellular sensitivity to insulin. Thus, they compared gene expression profiles in cultured mouse adipocytes exposed to tumor necrosis factor-α (TNF-α) or dexamethasone--two stimuli that produce insulin resistance but act through very different signaling mechanisms (the former through a cytokine receptor at the cell surface and the latter through a nuclear hormone receptor). Their analyses indicated that 18% of the genes that were similarly regulated in response to both treatments encoded products that influenced the abundance of reactive oxygen species (ROS) (radical forms of oxygen that are produced during cellular respiration or other enzymatic reactions and are known both to damage other molecules and to act as signaling molecules). Following this lead, the authors found that both dexamethasone and TNF-α caused increased intracellular accumulation of ROS. Furthermore, treatment of cultured cells with antioxidant molecules or expression of enzymes that remove ROS suppressed insulin resistance induced by dexamethasone and TNF. In a mouse model of obesity, chronic treatment of mice with a chemical antioxidant resulted in improved glucose homeostasis and sensitivity to insulin. The authors suggest that the relation of ROS to insulin sensitivity may have evolved because increased accumulation of ROS could be interpreted by the cell as an imbalance between substrate availability and oxidative capacity to which decreased insulin signaling (and thus decreased glucose uptake) would be an appropriate response. How various stimuli might converge on ROS generation and how ROS actually influence insulin signaling remain to be worked out, but in the meantime, the authors suggest that antioxidant therapy should be considered a therapeutic strategy to manage insulin resistance in the clinic.

N. Houstis, E. D. Rosen, E. S. Lander, Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944-948 (2006). [Online Journal]

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