Radboud University Nijmegen Medical Centre, Nijimegen Center for Molecular Life Sciences, Departments of Pharmacology and Toxicology, and Orthodontics and Oral Biology, Nijmegen, the Netherlands.
Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):458-63. doi: 10.1161/ATVBAHA.110.211789. Epub 2010 Nov 18.
In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM.
In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 μmol/L (0.4 mg/dL) to 64 μmol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed.
Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.
在 2 型糖尿病（T2DM）中，氧化应激导致内皮功能障碍。胆红素是一种强大的内源性抗氧化剂，在临床前实验中显著减轻内皮功能障碍。吉尔伯特综合征伴有轻微和终身的高胆红素血症，与通常的心血管死亡率风险的三分之一相关。阿扎那韦治疗引起的高胆红素血症与吉尔伯特综合征非常相似。因此，我们假设阿扎那韦治疗可改善 T2DM 中的氧化应激和血管炎症，改善内皮功能。
在一项双盲、安慰剂对照交叉设计中，我们通过 3 天的阿扎那韦治疗使 16 名患有 T2DM 的患者出现中度高胆红素血症。第四天，通过静脉闭塞体积描记术评估内皮功能。通过动脉内输注乙酰胆碱和硝酸甘油分别评估内皮依赖性和内皮非依赖性血管扩张。阿扎那韦治疗使平均胆红素水平从 7 μmol/L（0.4 mg/dL）增加到 64 μmol/L（3.8 mg/dL）。观察到血浆抗氧化能力（P<0.001）和内皮依赖性血管扩张（P=0.036）显著改善，以及血浆血管性血友病因子（P=0.052）降低。
实验性高胆红素血症与 T2DM 中的内皮功能显著改善相关。
