PATHOGENETIC MECHANISMS IN DIABETIC VASCULAR DISEASE

本申请中提出的研究的长期目标 旨在阐明糖尿病损伤血管的机制(S) 并导致临床上有意义的血管疾病。成长中的身体 证据表明：1)许多晚期并发症 糖尿病与葡萄糖到山梨醇的代谢增加有关。 通过醛糖还原酶，和2)醛糖还原酶连接， 糖尿病引起的血管损伤和山梨醇代谢 荷尔蒙调节的。设计了实验方案 实现以下具体目标：1)阐明 胰岛素缺乏与高血糖无关，反之亦然， 在糖尿病血管病变的发病机制中，2)阐明 组织肌醇和Na/K-ATPase水平降低的作用 介导糖尿病引起的血管内皮细胞增多的活性 渗透性，3)评估性的潜在机制 类固醇和甲状腺激素可能调节糖尿病 多元醇代谢和血管功能完整性的改变， 4)找出ALDO升高的机制(S) 糖尿病大鼠红细胞酮还原酶活性，5)~ 测定红细胞中醛酮还原酶的活性 与醛酮还原酶活性和/或血管相关 糖尿病患者坐骨神经、主动脉和眼部通透性的变化 大鼠，6)探讨醛固酮与 红细胞、青春期和血糖控制中的还原酶活性 在人类糖尿病患者中。 在大鼠身上的研究将广泛使用新的方法和 我们实验室开发的程序使我们有可能 评估激素、药理药剂和 组织代谢和血管代谢的代谢底物 体内通透性。激素和代谢的直接影响 基于这些参数的基质在新的造粒上进行了评估 在皮肤室中形成的组织，在其中测试物质 局部涂抹在组织上。评估血管通透性 通过渗透~(125)I-白蛋白。醛酮还原酶活性(AS 与环境中的多元醇水平相反)的红细胞和组织 通过测量半乳糖醇在 与半乳糖体外孵育。组织多元醇是定量的 使用电子电离气体作为其丁烷硼酸酯的衍生物 层析/质谱学。Na/K-ATPase活性为 用同位素方法进行评估。要获得的信息 从这些实验中应该提供重要的新见解 探讨糖尿病血管疾病的发病机制。

The long term objective of the studies proposed in this application is to elucidate the mechanism(s) by which diabetes injures vessels and causes clinically significant vascular disease. A growing body of evidence indicates that: 1) many of the late complications of diabetes are linked to increased metabolism of glucose to sorbitol by the enzyme aldose reductase, and 2) aldose reductase-linked, diabetes-induced vascular damage and sorbitol metabolism are hormonally modulated. The experimental protocols are designed to achieve the following specific aims: 1) to elucidate the role of insulin deficiency independent of hyperglycemia, and vice versa, in the pathogenesis of diabetic vascular disease, 2) to clarify the roles of decreased tissue levels of myo-inositol and Na/K-ATPase activity in mediating diabetes-induced increases in vascular permeability, 3) to assess potential mechanisms by which sex steroids and thyroid hormone may modulate diabetes-induced alterations in polyol metabolism and vascular functional integrity, 4) to identify the mechanism(s) responsible for increased aldo- keto reductase activity in erythrocytes of diabetic rats, 5) to determine whether aldo-keto reductase activity in erythrocytes correlates with aldo-keto reductase activity and/or vascular permeability changes in sciatic nerve, aorta, and eyes in diabetic rats, 6) to investigate the relationship between aldo-keto reductase activity in erythrocytes, puberty, and glycemic control in human diabetics. The studies in rats will make extensive use of new methods and procedures developed in our laboratory which make it possible to assess direct effects of hormones, pharmacologic agents, and metabolic substrates on tissue metabolism and vascular permeability in vivo. Direct effects of hormones and metabolic substrates on these parameters are assessed on new granulation tissue formed in skin chambers in which test substances are applied topically to the tissue. Vascular permeability is assessed by permeation of 125I-albumin. Aldo-keto reductase activity (as opposed to ambient polyol levels) of red cells and tissues is assessed by measurement of galactitol accumulation during incubation with galactose in vitro. Tissue polyols are quantified as their butaneboronate derivatives using electron ionization gas chromatography/mass spectrometry. Na/K-ATPase activity is assessed by use of isotopic method. The information to be gained from these experiments should provide important new insights into the pathogenesis of diabetic vascular disease.