Sullivan Alexander E, Courvan Meaghan C S, Ada Aaron W, Wasserman David H, Niswender Kevin D, Shardelow Emily M, Wells Emily K, Wells Quinn S, Freiberg Matthew S, Beckman Joshua A
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Biochemistry, University of Colorado, Boulder, Colorado, USA.
Endocrinol Diabetes Metab. 2025 Mar;8(2):e70031. doi: 10.1002/edm2.70031.
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.
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.
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.
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.
Short-term reduction of FFA concentration does not improve insulin-stimulated vasodilation in patients with metabolic syndrome.
ClinicalTrials.gov identifier: NCT00759291 and NCT00760019 (formerly NCT00762827).
血清游离脂肪酸（FFA）浓度升高与胰岛素抵抗相关，是代谢综合征的一个标志。胰岛素抵抗的一个病理特征是内皮功能受损。
研究使用阿西莫司（一种损害脂肪分解的烟酸衍生物）或柳氮磺吡啶（一种降低基础及炎症诱导脂肪分解的水杨酸盐）降低FFA对胰岛素介导的内皮依赖性血管舒张的影响。
这是一项对两项随机、双盲、安慰剂对照交叉试验的事后联合分析。招募了16名受试者（6名患有代谢综合征，10名对照），随机分为每6小时口服阿西莫司250mg，共7天或服用安慰剂。招募了19名受试者（13名患有代谢综合征，6名对照），随机分为接受柳氮磺吡啶4.5g/天，共4周或服用安慰剂。主要结局是FFA浓度与胰岛素介导的血管舒张之间的关联，通过基线时以及使用研究药物调节FFA后的静脉阻塞应变计体积描记法进行测量。
在基线时，FFA浓度（R = -0.35，p = 0.043）和胰岛素敏感性（稳态模型评估胰岛素抵抗指数：R = -0.42，p = 0.016，脂肪细胞胰岛素抵抗指数：R = -0.39，p = 0.025）可预测胰岛素介导的血管舒张。药物预处理后FFA水平显著降低（0.604 vs. 0.491 mmol/L，p = 0.036），而胰岛素水平、胰岛素敏感性和炎症标志物未改变。尽管药物治疗使循环FFA降低，但胰岛素刺激的血管舒张和胰岛素敏感性均未改善。
代谢综合征患者短期降低FFA浓度并不能改善胰岛素刺激的血管舒张。
ClinicalTrials.gov标识符：NCT00759291和NCT00760019（原NCT00762827）。
