Mittermayer Friedrich, Schaller Georg, Pleiner Johannes, Krzyzanowska Katarzyna, Kapiotis Stylianos, Roden Michael, Wolzt Michael
Department of Clinical Pharmacology, Medical University Vienna, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
J Clin Endocrinol Metab. 2007 Jul;92(7):2574-80. doi: 10.1210/jc.2006-2130. Epub 2007 May 1.
Free fatty acids (FFAs) cause insulin resistance and vascular endothelial dysfunction. The peroxisome proliferator-activated receptor gamma agonist rosiglitazone acts as insulin sensitizer and could exert vasoprotective properties by preservation of endothelium-dependent vasodilation.
We tested the effect of rosiglitazone on FFA-induced endothelial dysfunction of the forearm resistance vessels, insulin sensitivity, asymmetric dimethylarginine (ADMA), and high-sensitivity C-reactive protein concentrations in humans.
We conducted a double-blind, randomized, placebo-controlled parallel-group study at a university hospital.
Rosiglitazone 8 mg daily or placebo was administered to 16 healthy male subjects for 21 d. On the last day, triglycerides and heparin were infused iv to increase FFA plasma concentrations.
Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroglycerine were assessed using strain-gauge plethysmography at baseline, and on d 21 before and after 5 h of triglyceride/heparin infusion.
Forearm blood flow reactivity was not affected by rosiglitazone or placebo. Infusion of triglyceride/heparin substantially increased FFA concentrations (P < 0.001) and reduced endothelium-dependent vasodilation by 38 +/- 17% (P = 0.024). In the face of lower FFA elevation (P = 0.047 vs. controls), endothelium-dependent vasodilation was preserved in subjects receiving rosiglitazone (P = 0.016 vs. placebo). Endothelium-independent vasodilation and C-reactive protein were unchanged, whereas insulin sensitivity and plasma ADMA similarly decreased in both study groups after FFA elevation (both P < 0.05 vs. baseline).
Rosiglitazone mitigates the increase in FFA after infusion of triglyceride/heparin and prevents FFA-induced endothelial dysfunction. These effects are independent and possibly occur before any changes in insulin sensitivity and ADMA plasma concentrations in healthy subjects.
游离脂肪酸（FFA）可导致胰岛素抵抗和血管内皮功能障碍。过氧化物酶体增殖物激活受体γ激动剂罗格列酮可作为胰岛素增敏剂，并可能通过维持内皮依赖性血管舒张发挥血管保护作用。
我们测试了罗格列酮对人体FFA诱导的前臂阻力血管内皮功能障碍、胰岛素敏感性、不对称二甲基精氨酸（ADMA）和高敏C反应蛋白浓度的影响。
我们在一家大学医院进行了一项双盲、随机、安慰剂对照的平行组研究。
16名健康男性受试者每天服用8mg罗格列酮或安慰剂，持续21天。在最后一天，静脉输注甘油三酯和肝素以提高血浆FFA浓度。
在基线时以及第21天甘油三酯/肝素输注5小时前后，使用应变片体积描记法评估前臂血流对内皮依赖性血管舒张剂乙酰胆碱和内皮非依赖性血管舒张剂硝酸甘油的反应。
前臂血流反应性不受罗格列酮或安慰剂影响。输注甘油三酯/肝素可显著提高FFA浓度（P<0.001），并使内皮依赖性血管舒张降低38±17%（P=0.024）。在FFA升高幅度较低的情况下（与对照组相比，P=0.047），接受罗格列酮治疗的受试者的内皮依赖性血管舒张得以保留（与安慰剂相比，P=0.016）。内皮非依赖性血管舒张和C反应蛋白未发生变化，而在FFA升高后，两个研究组的胰岛素敏感性和血浆ADMA均同样降低（与基线相比，均P<0.05）。
罗格列酮可减轻输注甘油三酯/肝素后FFA的升高，并预防FFA诱导的内皮功能障碍。这些作用是独立的，并且可能在健康受试者的胰岛素敏感性和血浆ADMA浓度发生任何变化之前就已出现。
