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Clinical Trial
. 2025 Mar;8(2):e70031.
doi: 10.1002/edm2.70031.

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

Alexander E Sullivan  1 , Meaghan C S Courvan  2 , Aaron W Ada  1   3 , David H Wasserman  4 , Kevin D Niswender  5   6 , Emily M Shardelow  7 , Emily K Wells  1   3 , Quinn S Wells  1   3 , Matthew S Freiberg  1   8 , Joshua A Beckman  9
Affiliations
Clinical Trial

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

Alexander E Sullivan et al. Endocrinol Diabetes Metab. 2025 Mar.

Abstract

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).

Keywords: endothelial function; free fatty acid; insulin sensitivity; insulin‐mediated vasodilation; metabolic syndrome.

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Conflict of interest statement

A.W.A.: Dr. Aday reports receiving consulting fees from Aeglea outside of the current work; J.A.B.: Consulting: JanOne; DSMC for Janssen and Novartis. The other authors have nothing to report.

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Free fatty acid concentration (left), insulin sensitivity (middle) and adipose tissue insulin resistance (right) associate with forearm blood flow response to insulin stimulation after placebo pretreatment.
FIGURE 2
FIGURE 2
Free fatty acid (A) and triglyceride (B) concentrations were reduced by acipimox and salsalate.
FIGURE 3
FIGURE 3
Free fatty acid concentration (left), insulin sensitivity (middle) and adipose tissue insulin resistance (right) do not associate with forearm blood flow response to insulin stimulation after drug treatment.
See this image and copyright information in PMC

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