Prevention of fat-induced insulin resistance by salicylate

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involvin g IKK-beta. To test this hypothesis, we first examined insulin action and s ignaling in awake rats during hyperinsulinemic-euglycemic clamps after a li pid infusion with or without pretreatment with salicylate, a known inhibito r of IKK-beta. Whole-body glucose uptake and metabolism were estimated usin g [3-H-3]glucose infusion, and glucose uptake in individual tissues was est imated using [1-C-14]2-deoxyglucose injection during the clamp. Here we sho w that lipid infusion decreased insulin-stimulated glucose uptake and activ ation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylat e pretreatment prevented these lipid-induced effects. To examine the mechan ism of salicylate action, we studied the effects of lipid infusion on insul in action and signaling during the clamp in awake mice lacking IKK-beta. Un like the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infus ion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced d efects in insulin signaling and action and represent a potentially novel cl ass of therapeutic agents for type 2 diabetes.