Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-β. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-β. Whole-body glucose uptake and metabolism were estimated using [3-3H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-14C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1–associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-β. Unlike the response in wild-type mice, IKK-β knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-β prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.
Jason K. Kim, Yoon-Jung Kim, Jonathan J. Fillmore, Yan Chen, Irene Moore, Jongsoon Lee, Minsheng Yuan, Zhi Wei Li, Michael Karin, Pascale Perret, Steven E. Shoelson, Gerald I. Shulman
Metabolic parameters during basal and hyperinsulinemic-euglycemic clamp periods in the control, IKK-β KO, lipid-infused control, and lipid-infused IKK-β KO mice at ∼20 weeks of age