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PubMed1986

Hypoglycemia following insulin and proinsulin. A comparison.

The counterregulatory hormonal response to proinsulin-induced hypoglycemia was investigated in eight volunteers. Proinsulin cleared slower from the circulation than insulin. Hypoglycemia occurred slower (2P less than 0.005) and was prolonged, while the overall hypoglycemic activities were comparable. The antilipolytic effect of proinsulin was also prolonged (2P less than 0.001). The response of epinephrine to hypoglycemia was less pronounced after proinsulin (2P less than 0.05). The amount of epinephrine was correlated to the rate of fall in plasma glucose (P less than 0.005). The production of lactate induced by beta-stimulation was also correlated to the fall of glucose (P less than 0.005). The responses of prolactin (2P less than 0.02), norepinephrine (2P less than 0.02), cortisol, and growth hormone were attenuated following proinsulin. The decreases of serum potassium and serum phosphate (2P less than 0.05) were less pronounced. Symptoms like sweating (2P less than 0.01) and dizziness (2P less than 0.01) were milder after proinsulin. It is concluded that the rate of fall in glucose concentration determines the differing counterregulatory responses. We don't relate the differing counterregulatory responses to special insulin-like properties of proinsulin, but to the slower kinetics which is emphasized by the intravenous bolus injection.

3-Hydroxybutyric Acid↗

PubMed1997

Proinsulin targeting to the regulated pathway is not impaired in carboxypeptidase E-deficient Cpefat/Cpefat mice.

Sorting of proinsulin from the trans-Golgi network to secretory granules is critical for its conversion to insulin as well as for regulated insulin secretion. The proinsulin sorting mechanism is unknown. Recently, carboxypeptidase E (CPE) was proposed as a sorting receptor for prohormones. To know whether CPE is implicated in proinsulin sorting, pancreatic islets were isolated from CPE-deficient Cpefat/Cpefat mice and Cpefat/+ controls, pulse-labeled ([3H]leucine), and then chased in basal medium (90 min) to examine constitutive secretion followed by medium with secretagogues (60 min) to stimulate regulated secretion. Secretion of labeled proinsulin via the constitutive pathway was <2% even in Cpefat/Cpefat islets. After a 150-min chase, only 13% of radioactivity remained as proinsulin in Cpefat/+ islets compared with 46% in Cpefat/Cpefat islets, reflecting slower conversion. Regulated secretion was stimulated to an equal extent from Cpefat/+ and Cpefat/Cpefat mice with 20% of the total content of labeled (pro)insulin released during the 60-min stimulatory period. It is concluded that in CPE-deficient Cpefat/Cpefat mice, proinsulin is efficiently routed to the regulated pathway and its release can be effectively stimulated by secretagogues. CPE is thus not essential for sorting proinsulin to granules.

Animals↗

PubMed2003

Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels in islet beta-cells but not regulated via a positive feedback of secreted insulin.

Proinsulin biosynthesis is regulated in response to nutrients, most notably glucose. In the short term (</=2h) this is due to increases in the translation of pre-existing mRNA. However, prolonging glucose stimulation (24 h) also increases preproinsulin mRNA levels. It has been proposed that secreted insulin from the pancreatic beta-cell regulates its own synthesis through a positive autocrine feedback mechanism. Here the comparative contributions of translation and mRNA levels on the levels of proinsulin biosynthesis were examined in isolated pancreatic islets. Also, the autocrine role of insulin upon four beta-cell functions (insulin secretion, proinsulin translation, preproinsulin mRNA levels, and total protein synthesis) was investigated in parallel. The results showed that proinsulin biosynthesis is regulated, in the short term (1 h), solely at the level of translation, through an approximately 6-fold increase in response to glucose (2.8 mm versus 16.7 mm glucose). In the longer term, when preproinsulin mRNA levels have increased approximately 2-fold, a corresponding increase was observed in the fold response of proinsulin translation to a stimulatory glucose concentration (>/=10-fold). Importantly, neither exogenously added nor secreted insulin were found to play any role in regulating insulin secretion, proinsulin translation, preproinsulin mRNA levels, or total protein synthesis. The results presented here indicate that long term nutritional state sets the preproinsulin mRNA level in the beta-cell at which translation control regulates short term changes in rates of proinsulin biosynthesis in response to glucose, but this is not mediated by any autocrine effect of insulin.

Animals↗

PubMed1996

Synthesis and processing of genetically modified human proinsulin by rat myoblast primary cultures.

Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C-peptide (IFur) and between the C-peptide and A-chain (IIFur) and/or containing a histidine B10 to aspartic acid point mutation were subcloned into a mammalian expression vector (pCMV) containing the cytomegalovirus (CMV) promoter. The altered cleavage sites enable the insulin to be processed by the ubiquitous endoprotease furin. The histidine B10 to aspartic acid mutation creates a more stable form of insulin leading to an increase in insulin accumulation. Myoblasts transfected with a proinsulin cDNA construct mutated at all three sites (pCMV.IFur.IIFur.B10), a construct with only the furin sites (pCMV.IFur.IIFur), and a construct containing only the mutation at the B10 position (pCMV.B10) accumulated 852 +/- 16, 150 +/- 13, and 883 +/- 39 microU (pro)insulin/ml, respectively, in the culture medium during a 48-hr incubation. (Pro)insulin was detected in the culture medium within 2 hr post-transfection. Significant (pro)insulin release continued for 1 week and gradually diminished over a month. Approximately 50% of the proinsulin released from rat myoblasts transfected with pCMV.IFur.IIFur.B10 was completely processed into mature insulin based on densitometric analysis of autoradiographs of gels containing immunoprecipitated 35S-Cys-labeled (pro)insulin. However, only a trace of the proinsulin encoded by pCMV.B10 was processed. In an isolated rat adipocyte [14C]glucose oxidation assay, insulin released from myoblasts transfected with pCMV.IFur.IIFur.B10 was active biologically, displaying more biological activity than normal human insulin. Plasmid expression was studied by transfecting myoblasts with the beta-galactosidase (beta-Gal) gene in pCMV, allowing them to divide and fuse into multinucleated myotubes, followed by staining for beta-Gal. Approximately 80% of myotubes expressed beta-Gal. The results indicate that proinsulin encoded by genetically modified proinsulin cDNA is processed into mature insulin, which is secreted at high levels, making myoblasts a viable target cell for gene therapy of IDDM.

Animals↗

PubMed2003

Upstream AUGs in embryonic proinsulin mRNA control its low translation level.

Proinsulin is expressed prior to development of the pancreas and promotes cell survival. Here we study the mechanism affecting the translation efficiency of a specific embryonic proinsulin mRNA. This transcript shares the coding region with the pancreatic form, but presents a 32 nt extended leader region. Translation of proinsulin is markedly reduced by the presence of two upstream AUGs within the 5' extension of the embryonic mRNA. This attenuation is lost when the two upstream AUGs are mutated to AAG, leading to translational efficiency similar to that of the pancreatic mRNA. The upstream AUGs are recognized as initiator codons, because expression of upstream ORF is detectable from the embryonic transcript, but not from the mutated or the pancreatic mRNAs. Strict regulation of proinsulin biosynthesis appears to be necessary, since exogenous proinsulin added to embryos in ovo decreased apoptosis and generated abnormal developmental traits. A novel mechanism for low level proinsulin expression thus relies on upstream AUGs within a specific form of embryonic proinsulin mRNA, emphasizing its importance as a tightly regulated developmental signal.

3T3 Cells↗

PubMed1986

Hypersecretion of proinsulin does not explain the hyperinsulinaemia of patients with liver cirrhosis.

A radioimmunoassay using a proinsulin-specific antiserum that does not react preferentially with the split forms of proinsulin has been used to compare the response of circulating proinsulin to low (25 g) and high (75 g) oral glucose loads in healthy subjects and in patients with liver cirrhosis. The patients were divided into two groups: Group A (n = 7) with normal glucose tolerance and Group B with diabetic (n = 5) and impaired (n = 1) glucose tolerance. There was no apparent correlation between glucose tolerance and the results of quantitative liver function tests. In the fasted state, the concentrations of serum proinsulin did not differ significantly in patients of Group A (0.022 +/- 0.002 nmol/l) or Group B (0.026 +/- 0.004 nmol/l) from those in healthy subjects (0.021 +/- 0.002 nmol/l). After 75 g glucose, the rise in serum proinsulin to a maximum concentration of 0.082 +/- 0.012 nmol/l in patients of Group A and to 0.070 +/- 0.019 nmol/l in Group B was not significantly different at any time point up to 180 min from the rise in healthy subjects (to 0.063 +/- 0.005 nmol/l). After 25 g glucose, the response of serum proinsulin in Group B patients (maximum concentration 0.035 +/- 0.003 nmol/l) was not significantly different from that in healthy subjects (maximum concentration 0.032 +/- 0.003 nmol/l) but a slightly enhanced release was observed in the Group A patients (maximum concentration 0.049 +/- 0.003 nmol/l) that was significantly greater (P less than 0.05) at 60 min post-glucose. In contrast, the concentrations of serum immunoreactive insulin and immunoreactive C-peptide in all patients with cirrhosis were significantly elevated compared with healthy subjects both in the fasted state and at several time points following high and low oral glucose. In the fasted state, the serum proinsulin/C-peptide molar ratio, an index of the relative state of secretion of proinsulin and insulin, was significantly lower (P less than 0.05) in both groups of cirrhotic patients than in healthy subjects. After high and low glucose, this ratio fell in all patients and in the healthy subjects. We conclude that cirrhosis of the liver is associated with a hypersecretion of insulin but hyperproinsulinaemia does not contribute appreciably to the elevated concentration of immunoreactive insulin in the peripheral circulation.

Adult↗

PubMed1989

The effect of thyroid disease on proinsulin and C-peptide levels.

C-peptide and proinsulin levels were studied in hyper and hypothyroidism both pre and post-treatment and in comparison to matched normals. Fasting C-peptide was reduced in untreated hyperthyroidism (0.4 +/- 0.2 (mean +/- SEM) vs 0.7 +/- 0.2 nmol/l, P less than 0.05) but returned to normal levels following treatment. Fasting proinsulin was elevated in untreated hyperthyroidism (3.6 +/- 0.7 vs 2.4 +/- 0.5 pmol/l, P less than 0.05) also returning to normal after treatment. A similar pattern was seen after oral glucose. The increased proinsulin and reduced C-peptide suggest there may be a defect of proinsulin processing in hyperthyroidism. Fasting C-peptide was reduced in untreated hypothyroidism (0.4 +/- 0.1 vs 0.7 +/- 0.1 nmol/l, P less than 0.05) and also returned to normal after treatment. Fasting proinsulin did not differ significantly from controls. However, proinsulin was reduced after oral glucose (4.7 +/- 0.7 vs. 7.9 +/- 2.0 pmol/l, P less than 0.05) as was C-peptide (0.9 +/- 0.2 vs 2.6 +/- 0.3 nmol/l, P less than 0.05). Both returned to normal after treatment. These findings suggest there are abnormalities of proinsulin and C-peptide levels in both hyper and hypothyroidism.

Adult↗

PubMedDate not supplied

Increased maternal fasting proinsulin as a predictor of insulin requirement in women with gestational diabetes.

Circulating proinsulin was assessed during a 75g OGTT in 55 pregnant women who fulfilled WHO criteria for impaired glucose tolerance before the 32nd gestational week. Proinsulin was assayed retrospectively using a two-site immunoradiometric assay and immunoreactive insulin by radioimmunoassay. Of the 55 women, 19 required insulin treatment in addition to diet later in pregnancy. Fasting proinsulin concentrations were significantly higher in the 19 women who later required insulin treatment compared with the 36 women treated with diet alone (3.4 +/- 0.7 vs 1.8 +/- 0.2 pmol l-1, p < 0.005). There was no difference between the treatment groups of 60 and 120 min proinsulin values during the OGTT. Fasting plasma glucose and immunoreactive insulin were similar in the insulin-treated and diet-treated women and remained similar during the OGTT. No women within the insulin-treated group had a fasting plasma proinsulin value < 1.1 pmol l-1 in contrast with 12 women in the diet-treated group (p = 0.0123). Ten of the 19 insulin-treated women had a fasting plasma proinsulin > 2.5 pmol l-1 compared with 8 of the 36 diet-treated women (p = 0.0346). Fasting proinsulin values early in pregnancy have prognostic implications in women with gestational diabetes.

Adult↗

PubMed1986

Inhibition by proinsulin of endogenous C-peptide release in healthy man.

To determine the role of proinsulin on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in healthy subjects before and during infusion of human (HPI) and porcine (PPI) proinsulin at increasing rates for 70 min each (HPI, 328 and 656 micrograms X m-2 X h-1; PPI, 54, 134, and 268 micrograms/m-2 X h-1), while euglycemia was maintained by variable glucose infusion. By using this approach splanchnic C-peptide output was reduced by human proinsulin infusion from 143 +/- 16 (mean +/- SE) pmol/min to 111 +/- 18 and 75 +/- 11 pmol/min (P = 0.01). Simultaneously, arterial concentrations of C-peptide decreased from 716 +/- 40 pmol/l by 23 and 32%. Similar inhibition was induced by porcine PPI of splanchnic C-peptide output at an infusion rate of 268 micrograms X m-2 X h-1. Mean metabolic clearance rate was 2.7 and 3.7 ml X kg-1 X min-1 for HPI and PPI, respectively. Splanchnic glucose output was almost completely suppressed by human and porcine proinsulin at maximal infusion rates. This effect preceded both inhibition by proinsulin of splanchnic C-peptide output and stimulation of peripheral glucose utilization. We conclude that human and porcine proinsulin suppress endogenous insulin secretion at pharmacological concentrations. The observed constancy of the metabolic clearance rate of HPI demonstrates that its clearance remains a nonsaturable process up to supraphysiological HPI concentrations, while clearance of PPI appears to be subject to saturation. Furthermore, it appears that splanchnic glucose output responds earlier to proinsulin exposure than suppression of C-peptide release or stimulation of peripheral glucose utilization.

Adult↗

PubMed1987

Selective suppression of hepatic glucose output by human proinsulin in the dog.

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.

Animals↗

PubMed1995

Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo.

BACKGROUND: Fasting hyperinsulinemia (reflected by elevations in immunoreactive "insulin") is typical of patients with non-insulin-dependent diabetes mellitus (NIDDM) and is often associated with obesity and hypertension. The elevated concentrations detected are indicative not only of insulin but also of its immunologically cross-reactive precursors, including proinsulin. Fasting hyperinsulinemia appears to be associated with decreased fibrinolytic activity in blood, which results from increased activity of plasminogen activator inhibitor type-1 (PAI-1), a potential independent risk factor for coronary artery disease. Patients who were given proinsulin in a previous clinical study by others exhibited an increased incidence of cardiovascular events. Thus, a "proinsulin-PAI-1 axis" may predispose to coronary thrombosis. To define the possible presence of such an axis, this study was designed to determine whether insulin, its precursors, or both increase the concentrations of PAI-1 in rabbits in vivo. METHODS AND RESULTS: Equimolar proinsulin (n = 10), insulin (n = 11), C-peptide (n = 4), or vehicle alone (n = 10) was administered intravenously over 1 hour to euglycemic, conscious rabbits. Plasma PAI-1 activity increased 3.8-fold with proinsulin (P = .002) and 3.6-fold with insulin (P = .002). By contrast, no increase occurred after C-peptide or vehicle was administered. The increased PAI-1 activity was shown to be attributable to PAI-1 protein by reverse fibrin autography. As judged from changes in mRNA in tissues, proinsulin and insulin increased PAI-1 gene expression within 3 hours by 2.1- and 2.1-fold, respectively, in aorta (P = .025 each) and by 1.9- and 2.4-fold in liver (P = .015 and P = .001), with return of values to baseline within 24 hours (n = 4 experiments in each case). CONCLUSIONS: These results extend our previous observations from studies in vitro and suggest that hyperinsulinemia attributable to augmented concentrations of proinsulin and insulin in plasma increase plasma PAI-1 activity and may contribute to acceleration of atherosclerosis and impairment of coronary thrombolysis in patients with NIDDM.

Animals↗

PubMed1973

Metabolism of proinsulin, insulin, and C-peptide in the rat.

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.

Animals↗

PubMed1984

Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.

Familial hyperproinsulinemia, a hereditary syndrome in which individuals secrete high amounts of 9,000-mol wt proinsulin-like material, has been identified in two unrelated cohorts. Separate analysis of the material from each of the two cohorts had suggested that the proinsulin-like peptide was a conversion intermediate in which the C-peptide remained attached to the insulin B-chain in one case, whereas it was a conversion intermediate in which the C-peptide remained attached to the insulin A-chain in the other. To reinvestigate this apparent discrepancy, we have now used chemical, biochemical, immunochemical, and physical techniques to compare in parallel the structures of the immunoaffinity chromatography-purified, proinsulin-like peptides isolated from the serum of members of both families. Our results show that affected individuals in both cohorts secrete two-chained intermediates of proinsulin conversion in which the COOH-terminus of the C-peptide is extended by the insulin A-chain and from which the insulin B-chain is released by oxidative sulfitolysis. Analysis of the conversion intermediates by reverse-phase high-performance liquid chromatography using two different buffer systems showed that the proinsulin-related peptides from both families elute at a single position very near that of the normal intermediate des-Arg31, Arg32-proinsulin. Further, treatment of these peptides with acetic anhydride prevented trypsin-catalyzed cleavage of the C-peptide from the insulin A-chain, a result demonstrating the presence of Lys64 and the absence of Arg65 in both abnormal forms. We conclude that individuals from both cohorts with familial hyperproinsulinemia secret very similar or identical intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A chain and in which Arg65 has been replaced by another amino acid residue.

Acetic Anhydrides↗

PubMed1999

Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release.

Infiltration of immunocytes into pancreatic islets precedes loss of beta cells in type 1 diabetes. It is conceivable that local release of cytokines affects the function of beta cells before their apoptosis. This study examines whether the elevated proinsulin levels that have been described in prediabetes can result from exposure of beta cells to cytokines. Human beta-cell preparations were cultured for 48 or 72 hours with or without IL-1beta, TNF-alpha, or IFN-gamma, alone or in combination. None of these conditions were cytotoxic, nor did they reduce insulin biosynthetic activity. Single cytokines did not alter medium or cellular content in insulin or proinsulin. Cytokine combinations, in particular IL-1beta plus IFN-gamma, disproportionately elevated medium proinsulin levels. This effect expresses an altered functional state of the beta cells characterized by preserved proinsulin synthesis, a slower hormone conversion, and an increased ratio of cellular proinsulin over insulin content. The delay in proinsulin conversion can be attributed to lower expression of PC1 and PC2 convertases. It is concluded that disproportionately elevated proinsulin levels in pre-type 1 diabetic patients might result from exposure of their beta cells to cytokines released from infiltrating immunocytes. This hormonal alteration expresses an altered functional state of the beta cells that can occur independently of beta-cell death.

Adolescent↗

PubMed1990

Hypoglycemic potency and metabolic clearance rate of intravenously administered human proinsulin and metabolites.

Since circulating proinsulin has been suggested to be important in the pathogenesis of noninsulin-dependent diabetes, and biosynthetic human proinsulin (HPI) may have a therapeutic role in patients with diabetes mellitus, the biological activity of proinsulin metabolites is of potential significance. Moreover, recent studies have suggested that the majority of circulating proinsulin immunoreactivity consists of metabolites. We, therefore, compared the blood glucose-lowering ability and MCR of the two proinsulin metabolites des-(31,32)HPI and des-(64,65)HPI with intact HPI in seven anesthetized dogs after an overnight fast. Intravenous bolus injections of 12.5 micrograms HPI/kg BW and equimolar amounts of des-(31,32)HPI and des-(64,65)HPI were given on three separate occasions. In addition to blood glucose, des-(31,33)HPI, des-(64,65)HPI, and HPI were measured using an insulin RIA and peptide-specific standard curves. Kinetic parameters were derived by fitting two exponentials to the respective decay curves. The MCR of HPI (3.3 +/- 0.1 ml/kg.min) was significantly lower (P less than 0.05) than that of des-(64,65)HPI (6.4 +/- 0.6 ml/kg.min), but was not significantly different from that of des-(31,32)HPI (3.8 +/- 0.4 ml/kg.min). The MCR of biosynthetic insulin (17.2 +/- 1.8 ml/kg.min), as measured in three of the dogs, was higher than that of HPI or the two metabolites. The blood glucose-lowering ability (defined as nadir glucose/fasting glucose, expressed as a percentage) of des-(64,65)HPI (49.3 +/- 5.0%) was significantly greater (P less than 0.05) than that of intact HPI (87 +/- 2.2%), and the glucose-lowering ability of des-(31,32)HPI (75.2 +/- 3.8%) was intermediate. In conclusion, HPI metabolites are more biologically active than intact HPI. The extent of in vivo conversion of proinsulin to metabolites may enhance the biological activity of proinsulin and, thus, have physiological, pathophysiological, and therapeutic significance.

Animals↗

PubMed1975

Radioreceptor assay of insulin: Comparison of plasma and pancreatic insulins and proinsulins.

Porcine proinsulin, related intermediates and plasma immunoreactive insulin components have been studied by radioreceptor assay. Using the purified rat liver membrane or cultured human lymphocyte radioreceptor assay, porcine proinsulin is %5, split proinsulin 6% (54-55 split in connecting peptide) desdipeptide proinsulin 20% (deletion of amino acids 62 and 63 of connecting peptide) and desnonapeptide proinsulin 27% (deletion of amino acids 55-63 of connecting peptide) as active as porcine insulin in both assay systems; these values closely parallel the in vitro bioactivity of these preparations. In the lymphocyte radioreceptor assay the human plasma immunoreactive insulin-like component has the same potency as porcine insulin per immunoreactive unit, whereas the plasma immunoreactive proinsulin-like component is only 15% as active. Since both plasma immunoreactive components are somewhat less reactive than would be expected from puriified human insulin and proinsulin, the data suggest that both plasma components contain immunoreactive molecules that do not react in the radioreceptor assay.

Animals↗

PubMed1986

The effect of exogenous hyperinsulinemia on proinsulin secretion in normal man, obese subjects, and patients with insulinoma.

To examine possible feedback inhibition of insulin on proinsulin secretion, we measured serum proinsulin levels before and after 120 min of euglycemic hyperinsulinemia (90-100 mU/liter) in 11 normal and 7 obese hyperinsulinemic subjects and 6 patients with beta-cell adenoma (n = 4), carcinoma, or hyperplasia. Baseline proinsulin levels accounted for 19%, 14%, and 56% of the total immunoreactive insulin in the 3 groups, respectively. Compared to normal subjects, baseline proinsulin levels were elevated (P less than 0.02) by 4- and 6-fold in obese subjects and patients with autonomous insulin secretion, respectively, but there was an overlap between the groups. In both normal and obese subjects, hyperinsulinemia suppressed proinsulin secretion by 45-50% (P less than 0.02), whereas no response occurred in the patients. Thus, the 120 min values were clearly different in the patients and the normal or obese subjects. After removal of the adenoma in 4 patients, baseline proinsulin levels and the response to hyperinsulinemia were normalized, but they remained elevated after a partial pancreatectomy or tumor removal in the patients with beta-cell hyperplasia or carcinoma. Thus, proinsulin secretion is under negative feedback control of insulin in both normal man and hyperinsulinemic obese subjects. In patients with insulinoma or beta-cell hyperplasia, this control is lost.

Adenoma, Islet Cell↗

PubMed1993

Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance.

Conventional immunoassays to quantify insulin concentration do not differentiate between insulin and proinsulin. Thus, previous conclusions as to the relationship between the development of hyperglycemia in patients with noninsulin-dependent diabetes mellitus (NIDDM) and pancreatic insulin secretory function may have been confounded by not being able to determine the contribution made by plasma proinsulin to the putative measurements of plasma insulin concentration in these patients. The current study was initiated to address this issue by making specific measurements of plasma insulin, proinsulin, and C-peptide concentrations in 42 individuals: 14 with normal glucose tolerance, 12 with impaired glucose tolerance (IGT), and 16 with NIDDM. The study population was further subdivided into a nonobese (body mass index, < 30 kg/m2) and an obese (body mass index, > 30 kg/m2) group. Mixed meals were given at 0800, 1200, and 1800 h, and blood was removed at 0800 h (before the meal) and at hourly intervals from then until 1600 h. Plasma glucose concentrations throughout the sampling period were slightly, but significantly (P < 0.01), greater in patients with IGT than in normal individuals. Patients with NIDDM had markedly elevated glycemic excursions, greater than either of the other two groups (P < 0.002). Both plasma immunoreactive insulin and C-peptide concentrations from 0800-1600 h were higher (P < 0.002-0.001) in patients with either IGT or NIDDM than in the group with normal glucose tolerance. Although day-long plasma immunoreactive insulin and C-peptide concentrations were higher, on the average, in patients with IGT compared to those with NIDDM, the difference was not statistically significant. Plasma proinsulin concentrations were highest in patients with NIDDM (P < 0.002), lower in those with normal glucose tolerance (P < 0.002), and intermediate in patients with IGT. When the calculated "true" insulin concentration was determined by taking the proinsulin content into consideration, patients with IGT had the highest day-long levels, with the lowest values found in the control population (P < 0.002). Although absolute values varied as a function of obesity, the generalizations outlined above were found in both weight groups. These results show that ambient plasma proinsulin concentrations increase as glucose tolerance declines. However, true plasma insulin concentrations in response to mixed meals remain highest in patients with IGT, lowest in normal individuals, and intermediate in patients with NIDDM. Thus, previous conclusions that absolute day-long plasma insulin concentrations are not lower than normal in patients with NIDDM do not appear to result from an inability to differentiate true insulin from proinsulin.

Blood Glucose↗