Evidence that Somatomedin-C Is Degraded by the Kidney and Inhibits Insulin Degradation

Abstract

Studies were undertaken to determine the site of somatomedin-C degradation and the characteristics of the enzyme(s) responsible for this degradation. In the rat an important site of degradation is the kidney and somatomedin-C degradative activity occurs in 2 forms. The 1st, thought to be due to a sulfhydryl protease, is associated with the kidney plasma membrane and appears to be highly specific for somatomedin-C (Km = 1.6 .times. 10-8 M). The 2nd is found in cytosol and most effectively degrades reduced somatomedin-C (Km = 6.3 .times. 10-8 M). The data suggest that the cytosol activity is attributable to the so called insulin-glucagon protease since the 2 activities share characteristics consistent with a sulfhydryl protease and since both somatomedin-C and insulin have the capacity to inhibit the degradation of the other. In this regard, somatomedin-C appears to act as a competitive inhibitor of insulin degradation and has a Ki of 6 .times. 10-9 M. Chemically modified somatomedin-C derivatives and products of CNBr and tryptic cleavage, lost their ability to bind to the specific, cell membrane somatomedin-C receptors, but retained much of their capacity to inhibit insulin degradation in kidney cytosol. This suggests that the portion of the somatomedin-C molecule which is recognized by the cell membrane somatomedin-C receptor and is obligatory for its growth promoting actions is distinct from the portion of the molecule responsible for the reaction with the insulin-glucagon protease. These data further support earlier evidence of partial structural homology between somatomedin-C and insulin.