THE KIDNEY AND INSULIN

肾脏是胰岛素代谢的主要场所， 通过肾小球过滤和从血液中提取 管周循环 去除的胰岛素与特定受体结合 在管腔（L）和对管腔（CL）管状膜中，后者是 然后激活Na-K-ATP酶。 过滤后的胰岛素通过以下途径内化： 通过内吞作用，然后完全降解。 胰岛素是否暴露 对CL膜进行内化是未知的，但CL降解 确实会发生部分和完全降解产物的形成。 我们的具体目标是： 为了确定超微结构途径， 胰岛素在肾脏内的命运：特别是，我们的目标是（a）解决 关于过滤后的胰岛素被吸收后的途径的冲突 （B）评估从近端小管中提取的胰岛素是否 管周循环是内化的，还是仅仅局限于 细胞膜，和（c）评估溶酶体在肾细胞膜中的作用。 胰岛素降解 二. 为了评价胰岛素与 肾小管质膜受体 具体而言，我们的目标是：（a） 确定肾L和CL膜中的胰岛素受体是否 是否以同样的方式调节这些受体 与其他组织中的受体不同，（B）以确定是否 与糖尿病酮症酸中毒相关的可逆性高胰岛素尿是由于 改变的肾L膜胰岛素结合，（c）评价 胰岛素受体结合和Na-K-ATP酶激活在发病机制中的作用 不受控制的糖尿病胰岛素治疗后钠潴留。 将使用完整大鼠、离体灌注大鼠肾脏进行研究 和分离的肾质膜。 化学性或自发性 糖尿病将被使用。 方法学包括电子显微镜 放射自显影，亚细胞分级，凝胶过滤， 放射免疫测定和受体结合。 这些研究之所以特别重要，是因为 在胰岛素代谢中的作用。 通过使用复杂的 程序，新的信息将产生，应实现我们的长期 长期目标是提高对胰岛素代谢的理解，而不是 不仅在肾脏，而且在其他器官。 此外，新的洞察力， 将提供与糖尿病相关的肾功能变化。

The kidney is a major site of insulin metabolism removing the hormone from the circulation by means of glomerular filtration and by extraction from the peritubular circulation. Insulin removed binds to specific receptors in the luminal (L) and contraluminal (CL) tubular membranes, the latter is followed by activation of Na-K-ATPase. Filtered insulin is internalized by means of endocytosis and then degraded completely. Whether insulin exposed to the CL membrane undergoes internalization is unknown but CL degradation does occur with formation of partial and complete degradation products. Our specific aims are: I. To determine the ultrastructural pathway and fate of insulin within the kidney: In particular, we aim (a) to resolve the conflict regarding the pathway of filtered insulin after it is absorbed in the proximal tubule, (b) to assess whether insulin extracted from the peritubular circulation is internalized or whether it localizes solely to the cell membrane, and (c) to evaluate the role of lysosomes in renal insulin degradation. II. To evaluate the interaction between insulin and renal tubular plasma membrane receptors. In particular, we aim (a) to determine whether insulin receptors in renal L and CL membranes are regulated in the same manner and whether regulation of these receptors differs from that of receptors in other tissues, (b) to determine whether reversible hyperinsulinuria associated with diabetic ketoacidosis is due to altered renal L membrane insulin binding, (c) to evaluate the role of insulin receptor binding and activation of Na-K-ATPase in the pathogenesis of Na retention following insulin therapy of uncontrolled diabetes. Studies will be conducted with intact rats, isolated perfused rat kidneys and isolated renal plasma membranes. Rats with chemical or spontaneous diabetes will be used. Methodology includes electron microscopic autoradiography, subcellular fractionation, gel filtration, radioimmunoassay, and receptor binding. These studies are particularly significant because of the major role played by the kidney in insulin metabolism. By the use of sophisticated procedures, new information will be generated that should achieve our long term objectives of enhancing the understanding of insulin metabolism, not only in the kidney but also in other organs. In addition, new insight into changes in renal function associated with diabetes will be provided.