Circulating Proinsulin-like Material in Patients with Functioning Insulinomas

Gutman, R.; Lazarus, Norman R.; Penhos, J. C.; Fajans, Stefan S.; Recant, Lillian

doi:10.1056/nejm197105062841803

Cited by 83 publications

(26 citation statements)

References 14 publications

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“…The proinsulin content of extracted pancreas is less than 7% of the immunoreactive insulin level (26)(27)(28)(29)(30)(31)(32), while basal values in peripheral blood are higher, comprising approximately 20% of total IRI (7,(33)(34)(35)(36). Although it has been suggested that the higher circulating proinsulin content indicates preferential release of newly formed granules, which contain a higher proportion of proinsulin, our data on portal vein blood indicate that the ratio of proinsulin to insulin being secreted is similar to that present in the pancreas.…”

Section: Discussioncontrasting

confidence: 50%

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Horwitz¹,

Starr²,

Mako³

et al. 1975

J. Clin. Invest.

476

229

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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.

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Section: Discussioncontrasting

confidence: 50%

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Horwitz¹,

Starr²,

Mako³

et al. 1975

J. Clin. Invest.

476

229

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“…The heterogeneity is true for insulin. This is suggested by the facts that secretion of insulin-related peptides different in molecular size was demonstrated (Gutman et al 1971) and that dissociation between immunological and biological activity of insulin extracted from the tumors was observed (Ohneda et al 1974a). The precise process of insulin secretion from the insulinoma tissue remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Analysis of insulin secretion based on changes in plasma insulin and C-peptide in man.

Sakai

Ohneda

Nihei

et al. 1982

Tohoku J. Exp. Med.

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In order to clarify the mechanism of insulin secretion, responses of insulin (IRI) and C-peptide (CPR) in plasma to various stimuli were investigated in normal subjects and patients with diabetes mellitus, liver cirrhosis, chronic nephritis or insulinoma. The response of plasma IRI and CPR to oral glucose load was less marked in the mild and moderate diabetes groups than in the normal controls. Neither IRI nor CPR in the severe diabetes group responded to oral glucose. The patients with liver cirrhosis revealed an exaggerated and delayed response of IRI and CPR, and a lowered CPR/IRI ratio, indicating a remarkable response of IRI to glucose. In contrast, the patients with chronic nephritis showed a prominent rise of CPR alone. In the insulinoma patients, both plasma IRI and CPR increased after glucose load. In the response to glucose, there was approximately 30-min lag time between the peaks of IRI and CPR in the normal controls and the patients with various diseases. Following arginine infusion, plasma IRI and CPR increased in the normal subjects and the patients with moderate diabetes. In the normal subjects, plasma IRI reached a peak at 6 min and 3 min in response to tolbutamide and glucagon, respectively, which elicit an abrupt and sharp rise of insulin from B-cells. However, diabetic patients showed a minimal change in plasma IRI and CPR, whereas there was an exaggerated response of plasma IRI and CPR in insulinoma patients. In analysis of responses of plasma IRI and CPR to tolbutamide or glucagon, there was a lag time longer than 10 min in the normal subjects.The present study confirms the concurrent release of C-peptide from the B-cells in the secretion of insulin. In addition, it was suggested that insulin and C-peptide are mainly handled in the liver and the kidney, respectively.Furthermore, a longer lag time between the peaks of IRI and CPR in response to tolbutamide or glucagon did not necessarily indicate a simultaneous release of insulin and C-peptide from the B-cell, but a delayed release of the latter.glucose tolerance test; arginine; tolbutamide; glucagon The development of the immunoassay for insulin has made the measurement of a minute amount of insulin in plasma possible and has given much information concerning B-cell function of the pancreas. In 1967, Steiner and his co-workers discovered proinsulin from insulinoma tissues as well as from the normal rat

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“…The analogous des-dipeptide proinsulin intermediates have been identified by analysis of prpinsulin-containing fractions produced during the commercial manufacture of bovine and porcine insulin (4,6), by biosynthetic experiments involving the use of isolated pancreatic islets (7), and by in vitro studies involving the use of commercially available enzymes (8). Related forms, along with proinsulin, have been detected in large scale preparations of human insulin (9), in human insulinomas incubated with radiolabeled amino acids (1), and in human serum (10)(11)(12)(13)(14). Abnormal intermediates of conversion have also been identified in two families with insulin gene mutations and with familial hyperproinsulinemia (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Biochemical and clinical implications of proinsulin conversion intermediates.

Given¹,

Cohen²,

Shoelson³

et al. 1985

J. Clin. Invest.

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Since a complete map of insulin-related peptides in humans requires consideration of proinsulin, Arg32/Glu33-split proinsulin, Arg'5/Gly"-split proinsulin, des-Arg31,Arg32-proinsulin, desLys64,Arg65-proinsulin, and insulin, we applied high performance liquid chromatography coupled with radioimmunoassay to investigate the formation of proinsulin conversion intermediates in vitro and in vivo. Kinetic analysis of proinsulin processing by a mixture of trypsin and carboxypeptidase B (to simulate in vivo processes) revealed (a) a rapid decline in proinsulin concommitant with formation of conversion intermediates, (b) formation of desArg31,Arg32-proinsulin and des-Lys",Arge5-proinsulin in the ratio 3.3:1 at steady state, and (c) complete conversion of the precursor to insulin during extended incubation. Studies on normal human pancreas identified a similar ratio of des-Arg3',Arg32-proinsulin to des-Lys".,ArgA5-proinsulin (-3:1), whereas two insulinomas contained sizable amounts of des-Arg31,Arg32-proinsulin, but barely detectable amounts of des-Lys64,Arg'5-proinsulin. None of the tissues contained measurable quantities of Arg32/Glu33-or Arg'5/Gly"-split proinsulin. Analysis of plasma from three diabetic subjects managed by the intravenous infusion of human proinsulin revealed <1% processing of the circulating precursor to conversion intermediates and no processing of the precursor to human insulin. Nevertheless, analysis of plasma from the same subjects managed by the subcutaneous infusion of proinsulin revealed 4-11% processing of the precursor to intermediates that had the properties of des-Arg31,Arg32-proinsulin and Arge5/Gly"-split proinsulin. We conclude that (a) processing of proinsulin to insulin in vivo as in vitro likely occurs by preferential cleavage at the Arg32-Glu33 peptide bond in proinsulin, (b) proinsulin is inefficiently processed in the vascular compartment, and (c) subcutaneous administration of the precursor can result in the formation of conversion intermediates with the potential for contributing to biological activity.

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Circulating Proinsulin-like Material in Patients with Functioning Insulinomas

Cited by 83 publications

References 14 publications

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood.

Analysis of insulin secretion based on changes in plasma insulin and C-peptide in man.

Biochemical and clinical implications of proinsulin conversion intermediates.

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