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

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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).

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