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.