PATHOGENETIC MECHANISMS IN DIABETIC VASCULAR DISEASE

我的研究计划的长期目标是阐明 糖尿病晚期并发症的发病机制。几行 有证据表明，即使不是全部，也有许多代谢失衡 目前与糖尿病的早期血管和神经并发症有关 对葡萄糖诱导的新陈代谢有贡献或有后果 低氧(“高血糖低氧”)，即 NADH/NAD+，正常组织P02。之前的研究已经证实 这增加了山梨醇氧化成果糖的速度，而果糖与 NAD+减少为NADH，与增加的比率有关 乳酸/丙酮酸(细胞浆比的可靠参数 NADH/NAD+)，增加血流量和血管通透性。这些 氧化还原改变和血管功能障碍类似于相应的 缺血/缺氧心肌的改变与氧化还原和血管改变 与氰化物中毒有关。有几条证据支持 假设这些氧化还原变化可能启动合成增加的 一氧化氮(NO)，一种强大的血管扩张剂，可以调节血管 与所有这三种情况相关的功能障碍。具体的 本提案中概述的实验的目的是：(1)阐明 一氧化氮生成增加在糖尿病发病机制中的作用 并发症，(2)评估氨基胍的疗效。 发现新的一氧化氮合酶抑制剂，通过 糖酵解和山梨醇途径，以及(3)研究 血糖水平升高和山梨醇途径代谢对NO合成的影响 出自L-精氨酸。在无细胞提取液中和在 体外孵育的组织将通过L的转化进行监测- [14C]-精氨酸到L-瓜氨酸，cGMP水平的测定，以及 NO2(NO的氧化产物)的测量。潜力 这项研究的意义在于它可能提供的见解 关于糖尿病晚期并发症的发病机制，可能 帮助制定预防和预防的新方法 糖尿病并发症的治疗。

The long range goal of my research program is to elucidate the pathogenesis of the late complications of diabetes. Several lines of evidence indicate that many, if not all, of the metabolic imbalances currently linked to early vascular and neural complications of diabetes either contribute to or are the consequence of glucose-induced metabolic hypoxia ("hyperglycemic hypoxia"), i.e., an increase in the ratio of NADH/NAD+ despite normal tissue p02. Previous studies have established that increased oxidation of sorbitol to fructose, which is coupled to reduction of NAD+ to NADH, is associated with an increased ratio of lactate/pyruvate (a reliable parameter of the cytosolic ratio of NADH/NAD+) and increased blood flow and vascular permeability. These redox changes and vascular dysfunction are similar to corresponding changes in ischemic/hypoxic myocardium and to redox and vascular changes associated with cyanide poisoning. Several lines of evidence support the hypothesis that these redox changes may initiate increased synthesis of nitric oxide (NO), a potent vasodilator, which could mediate the vascular dysfunction associated with all three of these conditions. The specific aims of the experiments outlined in this proposal are to: (1) elucidate the role of increased NO production the pathogenesis of diabetic complications, (2) assess the effects of aminoguanidine, a newly discovered novel inhibitor of NO synthase, on metabolism of glucose via glycolysis and the sorbitol pathway, and (3) investigate the effects of elevated glucose levels and sorbitol pathway metabolism on NO synthesis from L-arginine. No synthase activity in cell free extracts and in tissues incubated in vitro will be monitored by the conversion of L- [guanidino14 C]-arginine to L-citrulline, measurement of cGMP levels, and measurement of NO2 (an oxidation product of NO). The potential significance of this research is that the insights it may provide regarding the pathogenesis of late complications of diabetes may contribute to the development of new approaches for the prevention and treatment of diabetic complications.