A B S T R A C T Concentrations of insulin, proinsulin, and C-peptide were measured in portal and peripheral venous blood in six nondiabetic, nonobese subjects. Portal vein samples were obtained by umbilical vein catheterization. Three subj ects were studied with intravenous infusion of 25 g glucose, and three with 30 g arginine. Insulin and proinsulin were determined in the insulin immunoassay after separation by gel filtration, and C-peptide was measured by direct immunoassay.With both glucose and arginine stimulation, portal vein levels of all three peptides peaked at 90-120 s after the onset of the stimulus. Relative increases in insulin concentration were greater than those of proinsulin or C-peptide. In peripheral venous blood, maximal levels of the three peptides were observed later (2-5 min), and the increase in insulin relative to proinsulin and C-peptide was not as great. At the time of peak secretion, portal vein insulin and C-peptide approached equimolar concentrations, and proinsulin, as measured against an insulin standard, comprised approximately 2.5% of the total immunoreactive insulin.After stimulation by glucose or arginine, portal insulin, proinsulin, and C-peptide levels were not correlated with the concentrations measured in simultaneously drawn peripheral samples. At all sampling times, however, significant correlation was found between insulin and C-peptide in both peripheral and portal blood. The results indicate that under the conditions studied, insulin and C-peptide are secreted in equimolar concentrations in man, and that proinsulin is secreted in the same proportion to insulin as found in the pancreas.
Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.
A B S T R A C T The removal of bovine proinsulin by the isolated perfused rat liver has been studied and the results compared with the removal of insulin. At high concentrations of insulin (> 180 ng/ml) the removal process was saturated and the ti varied between 35 and 56 min. With low initial insulin levels the disappearance followed first-order kinetics, the mean regression coefficient being -0.022, to 13.8 min, and the hepatic extraction 4.0 ml/min. The results with proinsulin were in striking contrast to these findings. At both high and low concentrations the hepatic removal of proinsulin was considerably slower, averaging 10-15 times less than that of insulin. Specific immunoassay techniques and gel filtration of samples taken from perfusions to which both labeled and unlabeled proinsulin had been added did not show conversion to either insulin or the C-peptide.Bovine and rat 'I-labeled proinsulins were degraded more slowly than bovine insulin-'1I by bovine and rat liver homogenates. Both proinsulin and insulin inhibited the degradation of insulin-tI, equimolar quantities of proinsulin being 2-5 times less effective than insulin.These results indicate significant differences in the capacity of the liver to remove and degrade insulin and proinsulin. The low hepatic extraction of proinsulin may account for its prolonged half-life in vivo and contribute to its relatively high plasma concentration in the fasting state. Furthermore this finding will have to be taken into account in the interpretation of changes in the proinsulin: insulin ratios in peripheral blood in a variety of metabolic situations.
The discovery of proinsulin and recognition of its intracellular conversion to insulin and C-peptide, which are stored and subsequently secreted together, have provided a simple method for monitoring β-cell function in insulinrequiring diabetics in whom insulin antibodies hinder measurement of immunoreactive insulin. Using an antiserum which reacts with antigenic determinants in human Cpeptide and this region in proinsulin and its intermediates we have measured C-peptide immunoreactivity (CPR) in unextracted serum and characterized its components. During oral glucose tolerance tests (OGTT) in nine healthy subjects, fasting serum CPR was 1.3 ± 0.3 ng./ml. and peaked at 4.4 ± 0.8 ng./ml. (60 min.). These values were positively correlated with immunoreactive insulin levels (IRI). CPR was undetectable in five newly diagnosd, untreated diabetics with fasting blood sugars above 200 mg./100 ml. and unmeasurable IRI. Similarly, serum CPR could not be measured in five ketosis-prone juvenile diabetics who had received insulin for longer than five years.' In contrast, fasting CPR was 2.7 ± 0.7 ng./ml. in twelve insulin-treated adult onset diabetics and rose to 5.0 ± 1.1 ng./ml. two hours after glucose. Several of these sera were extracted in acid-ethanol, gel-filtered. and measured against human proinsulin and C-peptide standards. Fasting proinsulin levels were markedly elevated, while C-peptide levels were comparatively low. Both components increased after glucose administration. As these diabetics had circulating insulin antibodies it was postulated that the elevated proinsulin levels represented circulating proinsulininsulin antibody complexes. Evidence favoring this possibility was derived from in vitro experiments in which human I-125-proinsulin was incubated with diabetic sera and the samples analyzed by gel filtration, paper electrophoresis and immune precipitation. Similar experiments with 1-125-C-peptide showed no evidence for preferential binding to plasma proteins in diabetic sera. Residual β-cell secretory capacity is thus present in many insulin-treated adult onset diabetics. The C-peptide immunoassay should facilitate the prospective study of β-cell function in these patients.
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