POLYOL PATHWAY & GLOMERULAR FILTRATION IN DIABETES

在受糖尿病影响的每个组织中， 发生并预示着以后的结构性功能障碍。 眼内，外周 神经和新生血管组织，实验性糖尿病， 激活多元醇途径，导致两种蛋白质的早期缺陷， 这些组织的功能特征和组成部分 组织肌醇，这是重要的，在维持活动的一个 磷脂酰肌醇快速翻转池。 该系统具有 在维持一部分哇巴因的 敏感的Na/K ATP酶活性。 肌醇 饱食和/或醛糖还原酶抑制逆转了 肌醇代谢和功能异常， 组织中 广泛的初步数据表明，肾 血液动力学也受到肌醇异常影响 补充肌醇或使用醛糖后的代谢 还原酶抑制剂山梨醇逆转肾血管舒张 早期实验性糖尿病大鼠，从而正常化 GFR。 这种血管舒张的早期血流动力学异常， 肾小球高血压，并已被提出是一个标志物， 并探讨了后期结构性心肌梗死的发病机制 恶化 我们的建议旨在审查 补充肌醇的这种明显的有益作用， 实验性糖尿病，并确定潜在的长期 这种干预对结构和功能的好处 在实验动物中观察到的长期 糖尿病 清除率和肾小球微穿刺测量 将在大鼠中进行，以确定 肌醇代谢对肾内血流动力学的影响 包括肾小球内压和肾小球通透性。 肾小球系膜细胞（现已成功地 在我们的实验室培养）将进行研究，以 定义肌醇代谢改变对各种 在特定组织中的细胞代谢组分 严格控制的环境。 系膜细胞收缩 对激动剂的反应将通过测量细胞内 形状、氧消耗和细胞钙。 细胞 将通过放射性示踪脉冲研究磷脂酰肌醇的周转 用薄层色谱和气相色谱定量法 色谱技术 成功完成这些 拟议的实验可以提供一个新的理解， 早期功能变化的发病机制， 临床或实验性糖尿病和潜在的新治疗方法 糖尿病肾病的早期症状有哪些

In each tissue affected by diabetes, an early functional alteration occurs and heralds later structural dysfunction. In eye, peripheral nerve, and neo-vascular tissue, experimental diabetes, by activating the polyol pathway, results in an early defect in both the functional characteristics of these tissues and in a component of tissue inositol that is important in maintaining the activity of a rapidly-turning-over pool of phosphatidylinositol. This system has been shown to be crucial in maintaining a portion of the ouabain sensitive Na/K ATPase activity of the involved tissue. Inositol repletion and/or aldose reductase inhibition reverse the defect in inositol metabolism and in the functional abnormality in these tissues. Extensive preliminary data suggests that renal hemodynamics are also influenced by this abnormality in inositol metabolism since inositol supplementation or the use of the aldose reductase inhibitor sorbitol reverses the renal vasodilation of early experimental diabetes in the rat and thus normalizes the GFR. This early hemodynamic abnormality of vasodilation and glomerular hypertension and has been proposed to be a marker for and a pathogenetic mechanism of the later structural deterioration. Our proposal seeks to examine the mechanisms of this apparent beneficial action of inositol supplementation in experimental diabetes and to determine the potential long term benefits of this intervention on the structural and functional deterioration seen in the experimental animal with long term diabetes. Clearance and glomerular micropuncture measurements will be carried out in the rat to determine the effect of alterations in inositol metabolism on intrarenal hemodynamics including intraglomerular pressure and glomerular permeability. Glomerular mesangial cells (which have now been successfully grown in culture in our laboratory) will be studied in order to define the effects of alterations in inositol metabolism on various components of cellular metabolism in a defined tissue under rigorously controlled circumstances. Mesangial cell contractile response to agonists will be examined by measuring change in cell shape, in oxygen consumption, and in cell calcium. Cell phosphatidylinositol turnover will be studied by radiotracer pulse chase and by quantitative thin layer chromatographic and gas chromatographic techniques. Successful completion of these proposed experiments could provide a new understanding of the pathogenesis of the early functional changes which occur in clinical or experimental diabetes and a potential new therapeutic approach to the prevention of diabetic nephropathy.