title: Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity.
abstract: We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7  h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48  h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.
authors: Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada.
authors: Sandra
authors: S
authors: Pereira
authors: Wen Qin
authors: WQ
authors: Yu
authors: María E
authors: ME
authors: Frigolet
authors: Jacqueline L
authors: JL
authors: Beaudry
authors: Yaniv
authors: Y
authors: Shpilberg
authors: Edward
authors: E
authors: Park
authors: Cristina
authors: C
authors: Dirlea
authors: B L Grégoire
authors: BL
authors: Nyomba
authors: Michael C
authors: MC
authors: Riddell
authors: I George
authors: IG
authors: Fantus
authors: Adria
authors: A
authors: Giacca
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004655:Emulsions; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D006493:Heparin; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010743:Phospholipids; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000008:administration & dosage / Q000627:therapeutic use*; D013024:Soybean Oil
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; C000606206:Nfkbia protein, rat; D010743:Phospholipids; C545823:soybean oil, phospholipid emulsion; D000072000:NF-KappaB Inhibitor alpha; D013024:Soybean Oil; D006493:Heparin; D012980:Sodium Salicylate