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 enhance oxidative stress. In contrast, no in vivo studies have addressed such a relationship. This four-part study aims at investigating the association between FFA and oxidative stress in healthy volunteers. The following experimental procedures were carried out: 1) determination and simple correlations among fasting plasma FFA, glucose, insulin, plasma thiobarbituric acid-reactive substance (TBARS), the ratio of reduced 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 concentrations, 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, body mass index, and fasting and 2-h plasma glucose concentrations (r = 0.43; P < 0.01). In the time-dependent study, plasma TBARS concentrations increased with the rise in plasma FFA concentrations. In the dose-response study, a progressive increase in fasting plasma FFA concentrations was achieved by varying the Intralipid infusion rate, which also caused plasma TBARS concentrations to increase progressively until they reached a plateau between the last two infusion rates (0.3 and 0.4 mL/min). A euglycemic hyperinsulinemic glucose clamp (insulin infusion rate, 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 disposal (WBGD). GSH infusion (15 mg/min for 360 min) had opposite effects on plasma TBARS concentrations and WBGD. A combined infusion of 10% Intralipid and GSH was associated with a stimulation of WBGD with a magnitude midway between that of 10% Intralipid and GSH infused separately. In conclusion, fasting plasma FFA seems to enhances oxidative stress, which might contribute to the disruptive effects of plasma FFA on insulin-mediated glucose uptake.