BIOCHEMICAL BASIS OF DIABETIC ANGIOPATHY

加速血管生成的关键病因 糖尿病中的疾病仍然未知。 内皮细胞 损害，作为持续高血糖症的一种克服，可能是一种 启动因素是必要的，但不足以 并发症的发展。 内皮细胞很可能 因为它经常表现为非胰岛素依赖性 促进葡萄糖转运并富含醛糖还原酶 活动，这两种现象是目标的特征 组织中 多元醇、肌醇代谢异常， Na ~+，K ~+-ATP酶活性在实验中已与 糖尿病周围神经、透镜和肾小球， 葡萄糖的代谢是相似的。 最近人们认识到， 磷酸肌醇代谢可能有助于调节Na+泵 功能 多元醇通路活性增加，肌张力异常， 肌醇代谢和并发症类似于那些在 糖尿病状态如白内障和周围神经 也是半乳糖毒性的一部分， 假设高糖环境本身足以引发 糖尿病组织损伤 本研究的目的是利用 培养的主动脉内皮细胞作为研究的模型， 糖尿病性血管病 在培养基中培养的内皮细胞 含有高浓度的葡萄糖或半乳糖， 表明多元醇途径活性增加， 肌醇，这两者都可以通过伴随地校正 与醛糖还原酶抑制剂一起孵育。 虽然减少了 这些细胞中的肌醇水平不会导致水平降低 磷脂酰肌醇，有一个显着的损害， 磷脂酰肌醇周转不能纠正 同时抑制醛糖还原酶。 这很重要 因为主流假说的主要原则 糖尿病中的肌醇代谢异常是肌醇 消耗是有害的，只是因为它会导致二次污染。 细胞磷脂酰肌醇耗竭导致缺陷性 Na+，K+-ATP酶活性的调节。 我们的研究表明， 磷酸肌醇代谢异常是另一个原因 葡萄糖或半乳糖水平升高的独立影响。 在这 研究我们将确定高糖水平的机制， 产生肌醇的消耗，即生化损伤 负责受损的磷酸肌醇营业额，以及如何两者 与电解质和水的稳态受损有关。 逆转 各种生化和生理异常 包括潜在的有缺陷的细胞增殖， 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.