BIOCHEMICAL BASIS OF DIABETIC ANGIOPATHY

血管加速的关键致病因素 糖尿病中的疾病仍不清楚。内皮细胞 损害，作为对持续性高血糖的征服，可能是一种 启动因素是必要的，但不是充分的 并发症的发展。内皮细胞是一种可能的 靶组织，因为它通常表现为非胰岛素依赖 促进葡萄糖转运，富含醛糖还原酶 活动，两种目标特有的现象 纸巾。多元醇、肌醇代谢异常及受损 Na+，K+-ATPase活性在实验中有关联 糖尿病周围神经、晶状体和肾小球 葡萄糖的代谢是相似的。它最近被认为是 肌醇磷脂代谢可能有助于调节钠泵 功能。多元醇途径活性增加，肌肉异常- 肌醇代谢和并发症类似于 糖尿病状态，如白内障和周围神经 功能障碍也是半乳糖毒性的一部分，支持 假设高糖环境本身就足以启动 糖尿病组织损伤。这项研究的目的是利用 体外培养的主动脉内皮细胞作为研究血管内皮细胞的模型 糖尿病血管病变。在培养液中培养内皮细胞 含有高浓度的葡萄糖或半乳糖会 表现出多元醇途径活性增加和细胞耗竭 肌醇，这两种都可以同时纠正 与一种醛糖还原酶抑制剂孵育。虽然减少了 这些细胞中的肌醇水平不会导致水平下降 磷脂酰肌醇，有显著的损害 磷脂酰肌醇周转不能通过 同时抑制醛糖还原酶。这事很重要 因为流行的假设的主要原则是关于 糖尿病患者的肌醇代谢异常是肌醇 耗尽是有害的，因为它会导致二次 细胞磷脂酰肌醇耗尽导致缺陷 Na+，K+-ATPase活性的调节。我们的研究表明 另一个原因是肌醇磷脂代谢异常。 葡萄糖或半乳糖水平升高的独立影响。在这 研究我们将确定高血糖水平 产生肌醇的消耗，这是一种生化损伤 对磷脂酰肌醇代谢受损负责，以及两者如何 与电解质和水分动态平衡受损有关。反转 各种生化和生理异常 包括潜在的缺陷细胞增殖将是 通过使用醛糖还原酶抑制剂或 补充肌醇和/或花生四烯酸。

The key etiologic factor responsible for accelerated vascular disease in diabetes mellitus remains unknown. Endothelial cell damage, as a conquence of sustained hyperglycemia, may be an initiating factor that is necessary but not sufficient for the development of the complication. The endothelium is a likely target tissue because it often manifests non-insulin dependent facilitated glucose transport and is enriched in aldose reductase activity, two phenomena which are characteristic of target tissues. Abnormal polyol, myoinositol metabolism and impaired Na+, K+-ATPase activity have been linked in the experimental diabetic peripheral nerve, lens and renal glomeruli where the metabolism of glucose is similar. It has recently been recognized that phosphoinositide metabolism may help to regulate Na+-pump function. Increased polyol pathway activity, abnormal myo- inositol metabolism and complications analogous to those seen in the diabetic state such as cataracts and peripheral nerve dysfunction are also part of galactose toxicity supporting the hypothesis that a high sugar milieu per se is sufficient to initiate diabetic tissue damage. The purpose of this study is to utilize aortic endothelial cells in culture as a model for the study of diabetic angiopathy. Endothelial cells cultured in a medium containing high concentrations of glucose or galactose will demonstrate increased polyol pathway activity and depletion of myo-inositol both of which may be corrected by concomitantly incubating with an aldose reductase inhibitor. While decreased myo-inositol levels in these cells does not lead to decreased levels of phosphatidylinositol, there is a significant impairment in phosphatidylinositol turnover which can not be corrected by simultaneous inhibition of aldose reductase. This is important because the major tenet of the prevailing hypothesis concerning abnormal myo-inositol metabolism in diabetes is that myo-inositol depletion is deleterious only because it will result in a secondary depletion of cell phosphatidylinositol leading to defective regulation of Na+, K+-ATPase activity. Our studies suggest that an abnormality in phosphoinositide metabolism is another independent effect of elevated glucose or galactose levels. In this study we will determine the mechanism whereby high sugar levels produce a depletion of myo-inositol, the biochemical lesion responsible for impaired phosphoinositide turnover and how both relate to impaired electrolyte and water homeostasis. Reversal of the various biochemical and physiological abnormalities including potential defective cell proliferation will be accomplished by using aldose reductase inhibitors or supplementation with myo-inositol and/or arachidonate.