DOES FREE FATTY-ACID INFUSION IMPAIR INSULIN ACTION ALSO THROUGH AN INCREASE IN OXIDATIVE STRESS

In vitro studies have demonstrated that free fatty acids (FFA) may enh ance oxidative stress. In contrast, no in vivo studies have addressed such a relationship. This four-part study aims at investigating the as sociation between FFA and oxidative stress in healthy volunteers. The following experimental procedures were carried out: 1) determination a nd simple correlations among fasting plasma FFA, glucose, insulin, pla sma thiobarbituric acid-reactive substance (TBARS), the ratio of reduc ed glutathione (GSH) to oxidized GSH, and lipid hydroperoxide (n=30); 2) time-dependent effect of FFA on plasma TBARS concentrations and GSH /oxidized GSH ratio (n=10); 3) dose-dependent effect of FFA on plasma TBARS concentrations (n=9); and 4) relationship among plasma FFA conce ntrations, plasma TBARS concentrations, and insulin action (n=11). The results demonstrate that fasting plasma FFA concentrations correlated with fasting plasma TBARS concentrations (r=0.65; P <0.001) and lipid hydroperoxide (r=0.79; P <0.001). The correlation between plasma FFA and TBARS remained significant even after adjustment for age, sex, bod y mass index, and fasting and 2-h plasma glucose concentrations (r=0.4 3; P <0.01). In the time-dependent study, plasma TBARS concentrations increased with the rise in plasma FFA concentrations. In the dose-resp onse study, a progressive increase in fasting plasma FFA concentration s was achieved by varying the Intralipid infusion rate, which also cau sed plasma TBARS concentrations to increase progressively until they r eached a plateau between the last two infusion rates (0.3 and 0.4 mL/m in). A euglycemic hyperinsulinemic glucose clamp (insulin infusion rat e, 10.2 pmol/kg . min for 360 min) was also performed. Simultaneous 10 % Intralipid (0.4 mL/min) infusion significantly enhanced plasma TBARS concentrations and inhibited insulin-stimulated whole body glucose di sposal (WBGD). GSH infusion (15 mg/min for 360 min) had opposite effec ts on plasma TBARS concentrations and WBGD. A combined infusion of 10% Intralipid and GSH was associated with a stimulation of WBGD with a m agnitude midway between that of 10% Intralipid and GSH infused separat ely. In conclusion, fasting plasma FFA seems to enhances oxidative str ess, which might contribute to the disruptive effects of plasma FFA on insulin-mediated glucose uptake.