Journal Article

The Role of Serum Free Fatty Acids in Endothelium‐Dependent Microvascular Function

Aday, Aaron W., Niswender, Kevin D., Shardelow, Emily M., Beckman, Joshua A., Sullivan, Alexander E., Wells, Quinn S., Courvan, Meaghan C. S., Wasserman, David H., Freiberg, Matthew S., Wells, Emily K.

2025

Overview

Background Elevated serum free fatty acid (FFA) concentration is associated with insulin resistance and is a hallmark of metabolic syndrome. A pathological feature of insulin resistance is impaired endothelial function. Objective To investigate the effect of FFA reduction with either acipimox, a nicotinic acid derivative that impairs lipolysis, or salsalate, a salicylate that reduces basal and inflammation‐induced lipolysis, on insulin‐mediated endothelium‐dependent vasodilation. Methods This was a post hoc, combined analysis of two randomised, double‐blind, placebo‐controlled crossover trials. Sixteen subjects were recruited (6 with metabolic syndrome and 10 controls) and randomised to acipimox 250 mg orally every 6 h for 7 days or placebo. Nineteen subjects were recruited (13 with metabolic syndrome and 6 controls) and randomised to receive salsalate 4.5 g/day for 4 weeks or placebo. The primary outcome was the association between FFA concentration and insulin‐mediated vasodilation, measured by venous‐occlusion strain‐gauge plethysmography at baseline and following FFA modulation with the study drugs. Results At baseline, FFA concentration (R = −0.35, p = 0.043) and insulin sensitivity (HOMA‐IR: R = −0.42, p = 0.016, Adipo‐IR: R = −0.39, p = 0.025) predicted insulin‐mediated vasodilation. FFA levels were significantly reduced after drug pretreatment (0.604 vs. 0.491 mmol/L, p = 0.036) while insulin levels, insulin sensitivity and inflammatory markers were unchanged. Despite a reduction in circulating FFA with drug therapy, neither insulin‐stimulated vasodilation nor insulin sensitivity improved. Conclusions Short‐term reduction of FFA concentration does not improve insulin‐stimulated vasodilation in patients with metabolic syndrome. Trial Registration ClinicalTrials.gov identifier: NCT00759291 and NCT00760019 (formerly NCT00762827) At baseline, free fatty acid concentration and insulin sensitivity predicted insulin‐mediated vasodilation. Acipimox and salsalate reduced free fatty acid concentration, but did not change insulin sensitivity and there was no association between the change in free fatty acids and insulin‐mediated vasodilation.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adult / Cardiovascular disease / Cross-Over Studies / Double-Blind Method / Drug dosages / endothelial function / Endothelium / Endothelium, Vascular - drug effects / Endothelium, Vascular - physiology / Endothelium, Vascular - physiopathology / Fatty Acids, Nonesterified - blood / Female / free fatty acid / Glucose / Humans / Hyperglycemia / Inflammation / Insulin / Insulin resistance / Insulin Resistance - physiology / insulin sensitivity / insulin‐mediated vasodilation / Laboratories / Male / Metabolic syndrome / Metabolic Syndrome - blood / Metabolic Syndrome - drug therapy / Metabolic Syndrome - physiopathology / Middle Aged / Oxadiazoles - pharmacology / Oxadiazoles - therapeutic use / Oxidative stress / Pyrazines / Salicylates - pharmacology / Salicylates - therapeutic use / Tumor necrosis factor-TNF / Vasodilation - drug effects / Vasodilation - physiology