The kidney removes insulin from the circulation by glomerular and peritubular clearance, thus exposing both the luminal and the contraluminal tubular surfaces to the hormone. In the proximal tubule, filtered insulin is internalized by means of pinocytosis and eventually localizes in the lysosomes. The fate of insulin removed from the peritubular circulation is less well understood. We previously reported that tubular uptake of insulin is a temperature-sensitive process consisting of two different systems. The system associated with the luminal aspect of the cell appears to be dependent on oxidative metabolism, whereas the system associated with the contraluminal aspect of the cell appears to be independent thereof. To further characterize renal tubular insulin uptake, a study was performed with (OCI) was 1336 ± 51 μl/min (SEM), glomerular filtration rate (GFR) was 1019 ± 54 fillmin, peritubular clearance of insulin was 317 ± 56 μl/min, fractional excretion of sodium (FEna) was 5.1 ± 0.7%, and fractional excretion of insulin (FEi) was 1.3 ± 0.6%. Addition of inhibitors of glycolysis (iodoacetate), Na-K-ATPase (ouabain), and lysosomal degradation (chloroquine) was associated with a significant increase of Fei (4.7 ± 0.4%, 6.4 ± 1.4%, and 13.9 ± 2.4%, respectively) and of FEna (28%, 43%, and 12%, respectively). By contrast acetazolamide with furosemide increased FEna to 39%, without altering FEi. Analysis of all data revealed no correlation between FEna and FEi, indicating that tubular insulin absorption is at least partly independent of sodium reabsorption. None of the inhibitors altered OCI, GFR, or peritubular clearance significantly. The above observations, together with our previously reported data, indicate that luminal insulin uptake is a temperature and chloroquine sensitive process that is dependent on metabolic energy. The source of this energy appears to be ATP, which is derived from oxidative metabolism and glycolysis. These characteristics, consistent with a process involving pinocytosis and lysosomal degradation, were not features of the contraluminal insulin uptake process.

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