Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo

Abstract

Recent evidence indicates that inflammatory pathways are causally involved in insulin resistance. In particular, IκBα kinase β (IKKβ), which can impair insulin signaling directly via serine phosphorylation of insulin receptor substrates (IRS) and/or indirectly via induction of transcription of pro-inflammatory mediators, has been implicated in free fatty acid (FFA)-induced insulin resistance in skeletal muscle. However, it is unclear whether liver IKKβ activation plays a causal role in hepatic insulin resistance caused by acutely elevated FFA. In the present study, we wished to test the hypothesis that sodium salicylate, which inhibits IKKβ, prevents hepatic insulin resistance caused by short-term elevation of FFA. To do this, overnight-fasted Wistar rats were subject to 7-h i.v. infusion of either saline or Intralipid plus 20 U/ml heparin (IH; triglyceride emulsion that elevates FFA levels in vivo) with or without salicylate. Hyperinsulinemiceuglycemic clamp with tracer infusion was performed to assess insulin-induced stimulation of peripheral glucose utilization and suppression of endogenous glucose production (EGP). Infusion of IH markedly decreased (P<0.05) insulin-induced stimulation of peripheral glucose utilization and suppression of EGP, which were completely prevented by salicylate co-infusion. Furthermore, salicylate reversed IH-induced 1) decrease in IκBα content; 2) increase in serine phosphorylation of IRS-1 (Ser 307) and IRS-2 (Ser 233); 3) decrease in tyrosine phosphorylation of IRS-1 and IRS-2; and 4) decrease in serine 473-phosphorylated Akt in the liver. These results demonstrate that inhibition of IKKβ prevents FFA-induced impairment of hepatic insulin signaling, thus implicating IKKβ as a causal mediator of hepatic insulin resistance caused by acutely elevated plasma FFA. © 2007 Society for Endocrinology.