Binding and degradation of 125I-insulin by rat hepatocytes.

Insulin interactions with liver plasma membranes. Independence of binding of the hormone and its degradation.

The renal extraction and excretion of bovine proinsulin, insulin, and C-peptide and the contribution of the kidney to their total metabolic clearance rate (MCR) were studied in the rat. Metabolic clearance rates were measured by the constant infusion technique and plasma and urine concentrations of each polypeptide were determined by radioimmunoassay. The MCR of insulin (16.4+/-0.4 ml/min) was significantly greater than that of either proinsulin (6.7+/-0.3 ml/min) or C-peptide (4.6+/-0.2 ml/min). Metabolic clearance rates were independent of plasma levels over a range of steady-state plasma concentrations varying from 1 to 15 ng/ml.In contrast to the differences in their metabolic clearance rates, the renal disposition of the three polypeptides was similar, being characterized by high extraction and very low urinary clearance. The renal arteriovenous difference of proinsulin, insulin, and C-peptide averaged 36, 40, and 44%, respectively, and was linearly related to their arterial concentration between 2 and 25 ng/ml. When glomerular filtration was markedly reduced or stopped by ureteral obstruction, the renal extraction of proinsulin, insulin, and C-peptide was invariably greater than the simultaneously measured extraction of inulin, indicating that these polypeptides are removed from the renal circulation by both glomerular filtration and direct uptake from peritubular capillary blood. The fractional urinary clearance of each polypeptide never exceeded 0.6%, indicating that more than 99% of the amount filtered was sequestered in the kidney. The renal removal of proinsulin and C-peptide from the circulation accounts for 55 and 69% of their metabolic clerance rates, while the renal contribution to the peripheral metabolism of insulin was smaller, averaging 33%. This difference is due to the fact that insulin, but not the other two polypeptides, is metabolized to a significant extent by the liver. These results define the renal handling of proinsulin, insulin, and C-peptide in the rat and indicate that in this species the kidney represents a major site for insulin metabolism and is the main organ responsible for the degradation of proinsulin and C-peptide.

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Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Effects of insulin, glucagon, and insulin/glucagon infusions on liver morphology and cell division after complete portacaval shunt in dogs

INSULIN degradation is a complex and incompletely, understood process at present. In terms of overall clearance and metabolism, the liver is responsible for more than half of the total insulin degradation, with kidney responsible for most of the rest. The peripheral tissues, fat and muscle, probably degrade the remainder of the insulin in the body, but the absolute contribution of these tissues to insulin turnover is uncertain. It now appears that peripheral tissues can serve as a reservoir for insulin, presumably by the hormone binding reversibly to membrane receptors. The function of this remains to be established. At a cellular level in most tissues, insulin degradation is initiated by the hormone binding to specific receptors. The hormone-receptor complex is processed, including internalization and degradation of at least some of the hormone-receptor complexes. The enzyme or enzymes involved in the degradative process have not been established, but three systems have been implicated: insulin protease,...

Insulin Metabolism and Degradation

Physiological Processes and Dynamics in the Disposition of Small and Large Doses of Biologically Active and Inactive 131I-Insulins in the Rat

Degradation of 131I-Insulins by Rat Liver STUDIES IN VITRO

Data on the disposition of insulin I 131 are reviewed and analyzed to determine the mechanisms responsible for insulin dispersion phenomena. The liver is indicated as the primary organ responsible for controlling plasma clearance rates by the following two methods: chemical reaction that degrades intact insulin supplied by the plasma, and the presence of a region that controls the rate at which insulin I 131 is made available to the reaction sites. The degradation reaction is apparently second order with respect to intact insulin I 131, so that combination of two insulin I 131 molecules with insulin glutathione transhydrogenase appears to be required for degradation to occur. A proposed model describing the insulin and glucose dispersion systems and the interaction between them is capable of explaining qualitatively how plasma insulin and glucose levels are maintained.

John W. Bartlett

Papers

Physiological Processes and Dynamics in the Disposition of Small and Large Doses of Biologically Active and Inactive 131I-Insulins in the Rat

Degradation of 131I-Insulins by Rat Liver STUDIES IN VITRO

Insulin-Glucose Dispersion and Interaction System: Liver Control Mechanisms