title: Does free fatty acid infusion impair insulin action also through an increase in oxidative stress?
abstract: 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.
authors.affiliation: Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Paolisso
authors.forename: A
authors.initials: A
authors.lastname: Gambardella
authors.forename: M R
authors.initials: MR
authors.lastname: Tagliamonte
authors.forename: F
authors.initials: F
authors.lastname: Saccomanno
authors.forename: T
authors.initials: T
authors.lastname: Salvatore
authors.forename: P
authors.initials: P
authors.lastname: Gualdiero
authors.forename: M V
authors.initials: MV
authors.lastname: D'Onofrio
authors.forename: B V
authors.initials: BV
authors.lastname: Howard
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D005978:Glutathione; D002118:Calcium