Recent evidence indicates that inflammatory pathways are causally involved in
insulin resistance. In particular, Ikappa Balpha
kinase beta (IKKbeta ), which can impair
insulin signaling directly via
serine phosphorylation of
insulin receptor substrates (IRS) and/or indirectly via induction of transcription of proinflammatory mediators, has been implicated in
free fatty acid (FFA)-induced
insulin resistance in skeletal muscle. However, it is unclear whether liver IKKbeta 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 IKKbeta , 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. Hyperinsulinemic-euglycemic 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 Ikappa Balpha 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 IKKbeta prevents FFA-induced impairment of hepatic
insulin signaling, thus implicating IKKbeta as a causal mediator of hepatic
insulin resistance caused by acutely elevated plasma FFA.