OXIDATIVE STRESS AND ATHEROSCLEROTIC COMPLICATIONS OF DIABETES

氧化应激在糖尿病血管并发症演变中的作用尚不清楚，部分原因是目前评估体内自由基生成的方法存在局限性。本研究将利用气相色谱/质谱仪(GC/MS)方法对两个结构不同的F2-异前列烷-8-epi-PGF2a-I进行测定。这些体内自由基催化的脂质过氧化的新标记物将与低密度脂蛋白的氧化性和内皮血管运动功能一起进行评估，以解决糖尿病中氧化应激增强的假设，即这是微血管或大血管疾病发生之前的假设。1型糖尿病伴和不伴视网膜病变的患者、2型糖尿病伴和不伴大血管病变的患者、非糖尿病起源的外周血管疾病的患者和适当的对照组的尿中F2-异前列腺素的排泄量将被测量。因为异前列腺素是从花生四烯酸酯化到磷脂的原位形成的，所以我们将分离低密度脂蛋白来测量低密度脂蛋白磷脂中含有8-epi-PGF2a和IPF2a-I的程度。我们还将评估低密度脂蛋白对氧化的敏感性，以及在铜诱导的氧化过程中低密度脂蛋白中形成F2-异前列腺素的时间过程。高分辨率、非侵入性的血管抗氧化剂、维生素E+C将会降低尿中F2-异前列腺素的排泄量，同时调节低密度脂蛋白对氧化的敏感性，恢复内皮血管的舒缩功能。这项研究的结果可能支持糖尿病氧化应激增加在血管并发症发生之前的假设，并可能表明抗氧化剂在补充其他治疗方法预防或改善糖尿病并发症方面的治疗作用。

The role of oxidative stress in the evolution of diabetic vascular complications is unclear, in part due to limitation of current methodology to assess free radical generation in vivo. The present study will utilize gas chromatography/mass spectrometry (GC/MS) methods for the measurement of two structurally distinct F2-isoprostanes, 8-epi-PGF2a-I. These novel markers of free radical catalyzed lipid peroxidation in vivo will be assessed in conjunction with LDL oxidizability and endothelial vasomotor function to address the hypothesis that oxidative stress is enhanced in diabetes mellitus and that this precedes the onset of micro or macrovascular disease. Urinary excretion of the F2-Isoprostanes will be measured in patients with type 1 diabetes with and without retinopathy; in patients with type 2 diabetes with and without macrovascular disease; in patients with peripheral vascular disease of non-diabetic origin and in appropriate controls. Because isoprostanes are formed in situ from arachidonic acid esterified to phospholipid, we will isolate LDL to measure the degree to which LDL phospholipids contain 8-epi-PGF2a and IPF2a-I. We will also assess the LDL susceptibility to oxidation and the time course of formation of F2-Isoprostanes in the LDL during copper-induced oxidation. Endothelial-dependent and endothelial-independent dilatation of the brachial artery will be measured by high-resolution, non-invasive vascular antioxidants, vitamins E+C, will depress urinary excretion of F2-Isoprostanes concomitantly with modulation of LDL susceptibility to oxidation and restoration of endothelial vasomotor function. The results of this study might support the hypothesis that increased oxidative stress in diabetes precedes the onset of vascular complications and might indicate a therapeutic role for antioxidants in complementing other therapeutic approaches to the prevention or amelioration of diabetic complications.