POLYOL PATHWAY & GLOMERULAR FILTRATION IN DIABETES

在每个受糖尿病影响的组织中，早期的功能改变 发生并预示着后来的结构性功能障碍。眼睛中，外周 神经和新生血管组织，实验性糖尿病，由 激活多元醇途径，导致两种疾病的早期缺陷 这些组织和组件的功能特征 一种组织肌醇，对维持细胞活性很重要 快速翻转的磷脂酰肌醇。这个系统有 已被证明对维持一部分哇巴因至关重要 敏感的受累组织Na/K-ATPase活性。肌醇 补充和/或抑制醛糖还原酶可逆转心肌细胞的缺陷 肌醇代谢与这些患者的功能异常 纸巾。大量的初步数据表明，肾脏 肌醇的这种异常也会影响血流动力学。 补充肌醇或使用醛糖后的代谢 还原酶抑制剂山梨醇逆转大鼠肾血管扩张 在大鼠早期实验性糖尿病，从而使正常 GFR。这种早期血流动力学异常的血管扩张和 肾小球性高血压，已被提议作为 以及后期构造的致病机制。 恶化。我们的建议旨在研究 肌醇补充剂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 长期给药的实验动物出现恶化 糖尿病。肾小球清除率和肾小球微穿刺术测量 将在大鼠身上进行，以确定其效果 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 在我们实验室培养的)将被研究，以便 明确肌醇代谢变化对多种疾病的影响 特定组织中的细胞代谢成分 严格控制的情况。系膜细胞收缩 对激动剂的反应将通过测量细胞的变化来检验。 形状、耗氧量和细胞钙。细胞 将用放射性示踪脉冲研究磷脂酰肌醇的周转 Chase及定量薄层层析和气相色谱 层析技术。成功完成这些任务 拟议中的实验可能会提供对 脑梗塞早期功能改变的发病机制 临床或实验性糖尿病和潜在的新疗法 预防糖尿病肾病的探讨。

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.