THE KIDNEY AND INSULIN

肾脏是胰岛素代谢的主要部位，将荷尔蒙从 通过肾小球滤过和从肾小球中提取 肾小管周围循环。去除的胰岛素与特定受体结合 在管腔(L)和对管膜(CL)中，后者是 其次是Na-K-ATPase的激活。过滤后的胰岛素被内化 内吞作用的手段，然后完全降解。胰岛素是否暴露于 对CL膜的内化作用尚不清楚，但CL的降解 在形成部分和完全降解产物时确实会发生。 我们的具体目标是：一、确定超微结构途径和 胰岛素在肾脏中的去向：特别是，我们的目标是(A)解决 关于胰岛素被过滤吸收后途径的矛盾 在近端小管，(B)评估从近端小管提取的胰岛素是否 肾小管周围循环是内在化的，还是仅仅局限于 以及(C)评估溶酶体在肾脏中的作用。 胰岛素降解。II.评估胰岛素和胰岛素之间的相互作用 肾小管质膜受体。特别是，我们的目标是(A) 确定肾脏L膜和CL膜上的胰岛素受体是否 以同样的方式进行调节，以及这些受体的调节 不同于其他组织中的受体，(B)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 改变肾L膜胰岛素结合力，(C)评价其作用 胰岛素受体结合和Na-K-ATPase激活在发病机制中的作用 未控制的糖尿病胰岛素治疗后钠离子滞留。 研究将在完整的大鼠、分离的灌流大鼠肾脏中进行。 和分离的肾细胞质膜。化学性或自发性大鼠 糖尿病将被使用。方法学包括电子显微镜 放射自显影，亚细胞分离，凝胶过滤， 放射免疫分析和受体结合。 这些研究特别有意义，因为它发挥了重要作用 由肾脏在胰岛素代谢中发挥作用。通过使用复杂的 程序，将生成新的信息，以实现我们的长期目标 学期目标是加强对胰岛素代谢的了解，而不是 不仅在肾脏，而且在其他器官也是如此。此外，对 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.