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Journal ArticleDOI

Clearance of porcine insulin, proinsulin, and connecting peptide by the isolated rat liver.

01 Mar 1970-Experimental Biology and Medicine (SAGE Publications)-Vol. 133, Iss: 3, pp 894-896
TL;DR: In the isolated rat liver perfusion system, the immunological half-life of crystalline single-component insulin was 17 min, and there was no significant clearance of either proinsulin or the connecting peptide that links the A and B chain of insulin in the proins insulin molecule.
Abstract: SummaryIn the isolated rat liver perfusion system, the immunological half-life of crystalline single-component insulin was 17 min. In contrast, there was no significant clearance of either proinsulin or the connecting peptide that links the A and B chain of insulin in the proinsulin molecule. There was also no evidence of conversion of proinsulin to insulin. This may, in part, explain the prolonged in vivo half-life of proinsulin relative to insulin.The authors are most grateful to Dr. M. A. Root (Lilly) for the proinsulin antibody, and to Dr. R. E. Chance (Lilly) for the purified proinsulin, connecting peptide, and single-component insulin used in this study. We also appreciate the excellent technical assistance of Mrs. Carla Gullickson, Miss Ellen Laschansky, and Mrs. Jeanette Teague.
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Journal ArticleDOI
TL;DR: Interaction of insulin with liver plasma membranes is a complex phenomenon that involves at least two processes, degradation and binding to receptors, and these two processes are largely independent and unrelated under a variety of conditions.

394 citations

Journal ArticleDOI
TL;DR: These results quantitate prehepatic insulin production and portal venous insulin concentration from an analysis of the behavior of C-peptide within the plasma in both the steady state and the nonsteady state in man.
Abstract: The prehepatic production of insulin in normal man was evaluated by kinetic analysis of connecting peptide (C-peptide) behavior in the plasma in men and women. Studies were performed during suppression of endogenous insulin secretion (induced by both fasting and exogenous insulin injection) as well as during stimulation of secretion (induced by oral glucose ingestion) and iv glucose injection. Least squares spline fitting of the C-peptide data by interactive computer analysis permitted evaluation of the precursor production of insulin using a two-compartment model for C-peptide removal. Basal prehepatic insulin production averaged 15-4 mU/70 kg.min in 20 subjects and was reduced to 0.9 +/- 2.2 mU/70 kg.min after 84 h of fasting. The injection of exogenous iv insulin resulted in suppression of endogenous production to 0 +/- 2.5 mU/70 kg.min. Maximum prehepatic insulin production induced by a 100-g oral glucose tolerance test was 91 +/- 1.2 mU/70 kg.min, with a cumulative hormone secretion of 11.4 +/- 2.0 U over the 5 h of observation. After the acute iv injection of 25 g glucose, production rose to 465 +/- 108 mU/70 kg.min at 2 min post injection and rapidly returned toward basal. Levels of insulin in the portal vein calculated from this analysis were markedly elevated relative to simultaneous peripheral venous levels. These results quantitate prehepatic insulin production and portal venous insulin concentration from an analysis of the behavior of C-peptide within the plasma in both the steady state and the nonsteady state in man.

391 citations

Journal ArticleDOI
TL;DR: Obese women had significantly greater prehepatic production and portal vein levels of insulin both basally and following glucose stimulation, and this increase correlated with the degree of adiposity but not with waist-to-hip girth ratio (WHR).
Abstract: The effects of obesity and body fat distribution on splanchnic insulin metabolism and the relationship to peripheral insulin sensitivity were assessed in 6 nonobese and 16 obese premenopausal women. When compared with the nonobese women, obese women had significantly greater prehepatic production and portal vein levels of insulin both basally and following glucose stimulation. This increase correlated with the degree of adiposity but not with waist-to-hip girth ratio (WHR). WHR, however, correlated inversely with the hepatic extraction fraction and directly with the posthepatic delivery of insulin. The latter correlated with the degree of peripheral insulinemia. The decline in hepatic insulin extraction with increasing WHR also correlated with the accompanying diminution in peripheral insulin sensitivity. Increasing adiposity is thus associated with insulin hypersecretion. The pronounced hyperinsulinemia of upper body fat localization, however, is due to an additional defect in hepatic insulin extraction. This defect is closely allied with the decline in peripheral insulin sensitivity.

365 citations

Journal ArticleDOI
TL;DR: The renal handling of proinsulin, insulin, and C-peptide in the rat is defined and it is indicated that in this species the kidney represents a major site for insulin metabolism and is the main organ responsible for the degradation ofproinsulin andC- peptide.
Abstract: 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.

276 citations

Journal ArticleDOI
TL;DR: The difference in the half-life of C-peptide in plasma between diabetics and normals suggests an altered kinetics of the disappearance of the peptide, while the overall metabolism, as expressed by the MCR, is similar.
Abstract: The metabolic clearance rate (MCR) of synthetic human connecting peptide (C-peptide) was measured with a single-dose injection technique in six normal and seven diabetic subjects and with a constant infusion technique in one normal subject. The MCR of C-peptide did not differ in normal subjects (4.4 ml/min per kg; range, 3.7-4.9) and in diabetic subjects (4.7 ml/min per kg; range, 3.7-5.8). Employment of both techniques in one subject gave similar MCR. The average half-life of C-peptide in plasma calculated from the last 1-h period of the single-dose injection studies was longer in the insulin-dependent diabetics (42.5 min; range, 39.4-48.5) than in the normal subjects (33.5 min; range, 24.9-45.3). These results indicate that the beta-cell secretory capacity of normal and insulin-dependent diabetic subjects can be compared by measuring the C-peptide concentration in peripheral venous plasma. The difference in the half-life of C-peptide in plasma between diabetics and normals suggests an altered kinetics of the disappearance of the peptide, while the overall metabolism, as expressed by the MCR, is similar.

226 citations