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

Background and Aims: We 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 Results: Thirty 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 60-390 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). Conclusion: This 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. Trial registered at clinicaltrials.gov, NCT01351324.