Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender

•The impact of raised NEFA on endothelial function and insulin sensitivity was studied.•NEFA elevation during the SFA drink reduced FMD while SFA + LC n-3 PUFA improved FMD.•Men had a 10% higher SI with SFA + LC n-3 PUFA than SFA, with SI similar in women.•Changes in FMD were not mirrored by changes in circulating NOx.•Gender mediated the effect of NEFA composition on both endothelial function and SI.

Background and aimsWe have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion.Methods and resultsThirty adults (mean age 27.8 y, BMI 23.2 kg/m2) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60 and 390 min. For the final 150 min, a hyperinsulinaemic-euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post-clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P = 0.027) whilst SFA + LC n-3 PUFA improved FMD at 240 min (P = 0.003). In males, insulin infusion attenuated the increase in FMD with SFA + LC n-3 PUFA (P = 0.049), with SI 10% greater with SFA + LC n-3 PUFA than SFA (P = 0.041).ConclusionThis study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway.This trial was registered at clinical trials.gov as NCT01351324 on 6th May 2011.