Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo.
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.
Park
Edward
E
Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
Wong
Victor
V
Guan
Xinyu
X
Oprescu
Andrei I
AI
Giacca
Adria
A
D000818:Animals; D004338:Drug Combinations; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D004338:Drug Combinations; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D014443:Tyrosine; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D005947:Glucose; D005990:Glycerol; D012980:Sodium Salicylate