Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 09/2001; 293(5535):1673-7. DOI: 10.1126/science.1061620
Source: PubMed


We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.

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    • "Heterozygous deletion of IKKβ protects mice from insulin resistance in diet-induced and genetic models of obesity (Yuan et al. 2001). Moreover, salicylate improved insulin signalling through IKKβ inhibition (Yuan et al. 2001). IKKβ was then explored further in different tissues using conditional knockout mice. "
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