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PubMed1990

Plasma proinsulin in first-degree relatives of type 2 diabetic subjects.

Glucose intolerant relatives of Type 2 diabetic subjects have impaired insulin secretory responses to glucose but their proinsulin secretion has not been assessed. Plasma intact proinsulin was measured in 101 normoglycaemic and glucose intolerant first-degree relatives of Type 2 diabetic subjects both fasting and one hour after an infusion of glucose of 5 mg glucose.kg ideal weight.min-1. Geometric mean (+/- SD) plasma proinsulin increased from 2.4 (+2.5-1.2) and increased to 4.5 (+4.2-2.1) pmol/l at 1 hour (p less than 0.001). Linear regression revealed no relationship of fasting or achieved proinsulin with sex or obesity and a non-significant trend towards increasing fasting and achieved proinsulin with age and fasting plasma glucose. Proinsulin was assessed as a ratio to the simultaneous plasma C-peptide to estimate the relative amounts of insulin and proinsulin secreted by the beta-cells. Analysis of partial correlation coefficients, controlling for age and obesity, showed that the Achieved Proinsulin/Achieved C-peptide ratio was related to both fasting (r = 0.27, p = 0.004) and achieved plasma glucose (r = 0.25, p = 0.008). Glucose intolerant relatives (n = 37) had a small but significant increase in relative proinsulin secretion compared with normoglycaemic relatives (n = 64) (Achieved Proinsulin/Achieved C-peptide 0.07 +/- 0.05 vs 0.04 +/- 0.02 p less than 0.01). This is in accord with abnormal beta cell function being an early feature of Type 2 diabetes but does not distinguish between a primary beta-cell abnormality and a secondary effect of mild hyperglycaemia.

Adult↗
PubMed1988

Action profile of biosynthetic human proinsulin trials with the BIOSTATOR in metabolically normal subjects.

Studies to examine the pharmacokinetics and pharmacodynamic properties of biosynthetic human proinsulin were conducted with the aid of the "glucose-controlled insulin infusion system BIOSTATOR". Seven metabolically normal healthy volunteers were given subcutaneous injections of 0.1 mg human proinsulin per kg body weight, and the subsequent behaviour of the serum proinsulin concentration was monitored over a period of 21 hours. The drop in the blood-sugar levels was counteracted by corresponding infusions of glucose by the BIOSTATOR via a special clamp technique. The intensity and frequency of the glucose infusions given by the BIOSTATOR equipment enable us to draw conclusions regarding the hypoglycaemic efficacy of human proinsulin. Two to three hours after the subcutaneous injection, the serum proinsulin concentration had reached its plateau-like maximum value. After approximately 5 hours it had dropped to 2/3 of the maximum, and after another 3 to 4 hours it had fallen further to 1/3 of the maximum. It returned virtually to its initial value after a total of 14 to 16 hours. The dextrose infusion rate calculated by the BIOSTATOR reflects these changes in the form of an "action profile". Proinsulin has a mean transit time (MTT) of 322 minutes. This is longer than the MTT of normal insulin (188 minutes) but markedly shorter than that of NPH insulin (625 minutes). If the hypoglycaemic effects of insulin and human proinsulin are compared on the basis of the areas under their respective action profile curves, the hypoglycaemic effect of 1 mg human proinsulin corresponds to 5.2 IU insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

The direct relationship of proinsulin-insulin hypersecretion to basal serum levels of cholesterol and triglyceride in myotonic dystrophy.

Excessive pancreatic insulin secretory responses to a variety of beta-cytotropic agents have been observed in 40 to 60 per cent of subjects with myotonic dystrophy; in addition, 25 to 30 per cent of affected persons manifest mild glucose intolerance, suggesting that circulating insulin may be biologically ineffective. To test this hypothesis, 8 men with myotonic dystrophy were challenged with a 100 gm. oral glucose load; responses were compared to an age, sex, weight-matched control group. Fasting serum immunoreactive insulin (IRI), cholesterol, and triglyceride levels in the myotonic group did not differ significantly from the controls. In contrast, fasting blood glucose and serum free fatty acid (FFA) levels in the myotonic group were significantly elevated above control, although still within the accepted normal range. Following oral glucose challenge, myotonic subjects exhibited mild glucose intolerance and excessive IRI response, but the FFA and serum alpha-amino nitrogen responses were comparable to control responses. Serum proinsulin was separated from insulin by gel filtration and quantitated by immunoassay. Overall, the proinsulin level in myotonic serum was not greater than the accepted normal level. The mean proinsulin level at the peak serum IRI response during the test was 18.6 +/- 4.1 per cent of the total IRI; 3 myotonic subjects responded with greater than 20 per cent proinsulin. The proinsulin secretory response correlated significantly with basal triglyceride (r = 0.972) and cholesterol (r = 0.794) levels but not with fasting glucose or FFA levels. Peak insulin response was also significantly correlated with triglyceride but not with cholesterol levels. Serum insulin-like activity (ILA) from myotonic dystrophic patients was assessed in vitro employing rat adipose tissue and skeletal muscle in the presence and absence of excess guinea pig anti-insulin serum. Comparison of suppressible insulin-like activity to immunoreactive insulin revealed that the mean biological recovery of serum insulin in these assay systems was 85 to 90 per cent, indicating that endogenous insulin was biologically active on both adipose tissue and skeletal muscle in vitro. We conclude that a biologically ineffective form of circulating insulin does not exist in myotonic dystrophy and that the pancreatic insulin response mechanism may be excessively sensitive, resulting in balanced hypersecretion of proinsulin and insulin. The highly significant correlation between proinsulin and serum triglyceride or cholesterol levels suggests that, in addition to insulin, proinsulin may also exert an important influence on lipid metabolism.

Adult↗
PubMed1996

A specific and highly sensitive time-resolved fluoroimmunoassay for human proinsulin.

We describe a time-resolved fluoroimmunoassay specific for human proinsulin using a combination of two high-affinity monoclonal antibodies, one against insulin and the other specific for intact proinsulin and for split 65-66 and des 64-65 proinsulin forms. The assay employs only 200 microl of serum, with a detection limit of 0.1 pmol/l. The intra-assay variation coefficient was less than 3% between 3 and 1000 pmol/l. There was 0% cross-reaction with insulin, C-peptide, split 32-33 and des 31-32 proinsulin. Serum concentration of proinsulin was analyzed in 50 subjects during an oral glucose tolerance test (10 non-obese control, 10 obese controls, 10 subjects with impaired glucose tolerance, 10 patients with type II diabetes mellitus (DM) and fasting blood glucose (FBG) < 140 mg/dl, and 10 patients with type II DM and FBG > 150 mg/dl). Mean fasting serum proinsulin levels measured by this assay in non-obese controls (0.84 - 0.90 pmol/l; 0.1-2.4 pmol/l) were lower than the results reported by other investigators. There was an increase of proinsulin related to obesity and increased glucose levels, suggesting that proinsulin levels increase with insulin resistance.

Adult↗
PubMed2003

Insulin, proinsulin and insulin resistance status in relation to lipid profiles among school children in Taiwan-The Taipei Children Heart Study.

PURPOSE: Evidence suggests that there may be a metabolic syndrome characterized by hyperinsulinemia or insulin resistance associated with increased cardiovascular disease risk. The purpose of this study is to evaluate insulin, proinsulin or insulin resistance to determine which is the best parameter to predict lipid profiles among children in Taiwan. METHODS: After multi-stage sampling, we randomly included 852 school children (415 boys and 437 girls) with a mean age of 13 yr in this study. We measured insulin and intact proinsulin levels by RIA (<0.2% cross-reactivity) and estimated insulin resistance index (IRI) using the homeostatic model assessment (HOMA) method. We used standard methods to measure atherosclerotic lipid profiles including total cholesterol (CHOL), triglyceride (TG), HDL-C, apolipoprotein A (ApoA), apolipoprotein B (ApoB), and lipoprotein[a] and calculated LDL-C and TCHR (total cholesterol to HDL-C ratio) levels. RESULTS: Girls had higher CHOL, LDL-C, ApoA and ApoB levels than boys (p < 0.001). There was no significant difference in insulin, proinsulin and IRI status between boys and girls. Among boys, insulin, proinsulin and IRI were positively correlated with TG, ApoB and TCHR and negatively related to HDL-C. Among girls, these associations were attenuated and became insignificantly for TCHR and HDL-C. After adjusting for potential confounders, IRI and insulin were still positively associated with TG and ApoB levels and negatively associated with HDL-C in boys. However, in girls, proinsulin and insulin were positively associated with TG only. Finally, in the stepwise regression analyses, IRI was a better predictor of TG, HDL-C, and ApoB than insulin or proinsulin in boys. However, in girls, proinsulin was a stronger predictor than insulin or IRI for TG and TCHR. CONCLUSION: From this study, we found that IRI (in boys) and proinsulin (in girls) levels are generally more significant and stronger parameters than insulin for predicting lipid profiles among children in Taiwan.

Adolescent↗
PubMed1971

Circulating insulin: th proinsulin-like properties of "big" insulin in patients withou islet cell tumors.

When plasma is filtered on Sephadex G-50, insulin immunoreactivity is recovered in two peaks. "Big" insulin, the higher molecular weight component, and "little" insulin, the lower molecular weight component, have elution volumes that correspond to those of proinsulin-(125)I and insulin-(125)I respectively. When plasma was extracted with acid ethanol and filtered in 1.0 M acetic acid, the patterns and proportions of "big" and "little" insulin were indistinguishable from those obtained by filtration of whole plasma in neutral buffer. When "big" insulin was isolated from plasma and mixed with a tracer of porcine proinsulin-(125)I, trypsin converted the "big" insulin immunoreactivity to the gel filtration pattern of "little" insulin in the same way that it converted the proinsulin radioactivity. More than 90% of both "big" insulin and proinsulin were converted at optimal trypsin concentrations. Our present guinea pig anti-insulin serum failed to distinguish "big" from "little" but a porcine proinsulin anti-serum, under appropriate conditions of assay, reacted strongly with "big" insulin but not at all with "little." When tested on isolated fat cells, "little" insulin had the same bioactivity as porcine insulin, whereas "big" insulin had the same low activity as porcine proinsulin. These studies suggest that "big" insulin represents either single-chain proinsulin and/or a proinsulin intermediate that has similar low bioactivity.

Adenoma, Islet Cell↗
PubMed1995

In vivo iodination of a misfolded proinsulin reveals co-localized signals for Bip binding and for degradation in the ER.

The signal for degradation of proteins in the endoplasmic reticulum (ER) is thought to be the exposure of internal domains which are buried when the protein has adopted its correct conformation and which are also exposed in assembly intermediates. This raises the question of why the intermediates are not degraded. We developed a system based on the peroxidase-catalyzed iodination of tyrosine residues which continuously monitors the exposure of internal domains of proinsulin. In CHO cells this system discriminated between assembly intermediates of wild type (wt) proinsulin and misfolded proinsulin, as shown by the exclusive iodination of a misfolded mutant which was finally degraded in the ER. Iodination in vitro showed that the assembly intermediates of wt proinsulin also exposed internal domains. This iodination was inhibited by the addition of the molecular chaperone Bip which was co-immunoprecipitated with proinsulin in CHO cells. The results obtained with the mutant proinsulin support the assumption that exposed internal domains represent the signal for degradation in the ER. Observations of wt proinsulin show that Bip masks internal domains of normal assembly intermediates during the entire assembly process, thereby suppressing their degradation. We propose that internal domains contain co-localized signals for Bip binding and for degradation.

Adenosine Triphosphate↗
PubMed1996

Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study.

We studied the intra-individual variation in plasma glucose, specific serum insulin and serum proinsulin concentrations, measured by two 75-g oral glucose tolerance tests in an age, sex, and glucose tolerance stratified random sample from a 50-74-year-old Caucasian population without a history of diabetes mellitus. The intra-individual variation was assessed by the standard deviation of the test-retest differences (SDdif). For subjects with normal (n = 246), impaired glucose tolerance (n = 198), and newly detected diabetes (n = 80) classified at the first test, the following (SDdif/median level of individual average scores) were found: fasting glucose: 0.4/5.4, 0.5/5.9 and 0.7/7.2 mmol/l; 2-h glucose: 1.3/5.6, 1.8/8.5 and 2.3/12.8 mmol/l; fasting insulin: 23/76, 32/89 and 30/116 pmol/l; 2-h insulin: 190/303, 278/553 and 304/626 pmol/l; fasting proinsulin: 4/8, 6/13 and 9/18 pmol/l; 2-h proinsulin: 19/49, 23/84 and 33/90 pmol/l, respectively. In both glucose, proinsulin and insulin concentrations the total intra-individual variation was predominantly determined by biological variation, whereas analytical variation made only a minor contribution. The SDdif can easily be interpreted, as 95% of the random test-retest differences will be less than 2.SDdif, or in terms of percentage, less than (2.SDdif/median level of individual average score) 100. Therefore, for subjects with normal glucose tolerance, 95% of the random test-retest differences will be less than 15% (fasting glucose), 46% (2-h glucose), 61% (fasting insulin), 125% (2-h insulin), 100% (fasting proinsulin) and 78% (2-h proinsulin) of the median value of the individual average scores. No substantial independent association of either age, gender or obesity with the intra-individual variation in glucose, proinsulin, or insulin concentrations was found.

Anthropometry↗
PubMed1979

Measurement of human proinsulin by an indirect two-site immunoradiometric assay.

An indirect two-site immunoradiometric assay is described for the measurement of human proinsulin in plasma. Polyethylene tubes coated with purified guinea-pig antibodies to insulin were used to extract proinsulin and insulin from plasma. Rabbit antibody to human C peptide was then added to react with the C-peptide moiety of the bound proinsulin. The uptake of this antibody was measured by the subsequent binding of 125I-sheep antibody to rabbit IgG. The binding of radioactivity to the tubes was a function of the proinsulin concentration in the sample. The sensitivity of the assay was 0.006 pmol/ml. Only 200 microliters of plasma was required in the assay and the 125I-labelled antibody was produced from readily available reagents. The polyethylene tubes remained stable for at least 5 months after coating. The mean fasting proinsulin level was 0.009 pmol/ml in sixteen normal subjects and 0.025 pmol/ml in twelve maturity onset diabetics. Oral glucose produced an 8 fold increase in proinsulin concentration but a decline in the plasma proinsulin/insulin molar ratio. Four patients with insulinoma had extremely elevated proinsulin levels and proinsulin/insulin ratios.

Adenoma, Islet Cell↗
PubMed1989

Receptor binding and biologic activity of biosynthetic human insulin and mini-proinsulin produced by recombinant gene technology.

Human insulin and its precursor, mini-proinsulin, made with a new biosynthetic method, were tested for their receptor binding, biologic action, and antibody binding ability. The structure of mini-proinsulin is similar to that of proinsulin with a shortened C-peptide, B(1-29)-Ala-Ala-Lys-A(1-21) insulin. The ability of biosynthetic human insulin to bind to receptors, to stimulate 2-deoxyglucose uptake in isolated adipocytes, and to bind to insulin antibody was comparable to that of semisynthetic human insulin. The ability of mini-proinsulin to bind to insulin receptors and to stimulate 2-deoxyglucose uptake in adipocytes was 0.5 and 0.2% that of human insulin, whereas the corresponding abilities of proinsulin were 5 and 3%, respectively. Despite having less receptor binding and biologic activity, mini-proinsulin demonstrated higher affinity for the insulin antibody than did proinsulin. These results suggest that biosynthetic human insulin behaves similarly to semisynthetic human insulin in its receptor binding and biologic activity, and that the shortened C-peptide region reduces receptor binding by fixing or covering the N-terminal region of the A chain, which is important for receptor binding.

Adipose Tissue↗
PubMed1995

Elevated ratio of summed serum proinsulin to insulin response after oral glucose load in type 2 diabetes decreases following sulfonylurea treatment.

We showed previously that the disproportionate elevation of serum proinsulin at fasting and after glucose ingestion in Type 2 diabetes is reduced to nearly normal after improvement of glycemic control by diet therapy. In this study, we investigated the effect of sulfonylurea (SU) treatment on serum proinsulin levels and proinsulin/insulin ratio (PI/I) during oral glucose tolerance test in patients with Type 2 diabetes. Thirteen diabetic patients (age 56 +/- 9 years, body mass index 22.4 +/- 1.9 kg/m2, mean +/- SD) were examined by 75 g oral glucose tolerance test (OGTT) before and after glycemic control by SU therapy. Mean interval of two OGTTs was 126 days. Serum proinsulin was measured by the radioimmunoassay using a human proinsulin-specific antiserum. When glycemic control improved after SU therapy (mean fasting plasma glucose 11.5 and 6.0 mmol/l, before and after SU treatment), fasting insulin, proinsulin and PI/I ratio did not change significantly. Insulin response during OGTT markedly increased after SU therapy. Summed value of insulin (sigma I) increased from 634 to 1064 pmol/l after SU (P < 0.01), whereas summed proinsulin (sigma PI) did not change significantly (146 and 159 pmol/l), resulting in a significant decrease in sigma PI/sigma I (23.6-15.1%, P < 0.05). We conclude that the disproportionate elevation of proinsulin during OGTT in patients with Type 2 diabetes can be reduced after glycemic control by SU treatment, chiefly by a selective increase in insulin response.

Administration, Oral↗
PubMed1983

Synthesis of a human insulin gene. VI. Expression of the synthetic proinsulin gene in yeast.

The construction of plasmid vectors for the controlled expression of a synthetic human proinsulin gene in the yeast Saccharomyces cerevisiae is described. Attempts to express the proinsulin gene using the yeast ADH1 promoter alone did not yield detectable levels of proinsulin. Successful expression was achieved when the proinsulin gene was fused with the promoter and protein leader sequence of the GAL1 gene (coding for yeast galactokinase) in the yeast-Escherichia coli plasmid vector pYT7810. Two different-length leader sequences were employed; the longer leader (about 280 amino acids, fusion plasmid pPS13) gave about five times greater expression than the shorter leader fusion (30 amino acids, plasmid pPS5). Both fusions gave soluble protein products, and the proinsulin could be cleaved by cyanogen bromide treatment from the leader polypeptide. Proinsulin was detected by radioimmunoassay for human C-peptide only in cells induced with galactose, and was not detected in the gene fusions that were out of phase with the GAL1 leader sequence. Methods of improving the level of expression of the proinsulin gene in yeast using this system are discussed.

Amino Acid Sequence↗
PubMed1993

Analysis of proinsulin and its conversion products by reversed-phase high-performance liquid chromatography.

Proinsulin is synthesized in the beta-cells of the endocrine pancreas, one of the four cell types found in the islets of Langerhans. Specific enzymatic cleavage of proinsulin results in the formation of equimolar amounts of insulin and C-peptide, via several intermediate split-proinsulin forms. Most mammals produce a single insulin, but in rodents two non-allelic insulin genes are expressed. There is an inverse ratio between the two insulins in rats and mice, the reason for this being unknown. It has been suggested that differences in transcription, translation (biosynthesis) and/or posttranslational processes (enzymatic conversion, intracellular degradation) could be possible explanations. Elevated amounts of proinsulin-immunoreactive material (PIM) have been described to occur in various conditions/diseases, suggesting alterations in beta-cell function, but the composition of the secreted PIM (intact proinsulin or its intermediates) has been incompletely determined. Studies of the biosynthesis of proinsulins and their conversion with the purpose of revealing some of these points depend on accessible reversed-phase high-performance liquid chromatographic (RP-HPLC) analyses capable of separating all the relevant, closely related polypeptides involved. This review will deal with the optimization of the RP-HPLC separations as well as sample preparation and recovery. Applications of the selected methods in the study of proinsulin biosynthesis and its conversion will also be presented.

Animals↗
PubMed1998

Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation.

Disproportional hyperproinsulinemia is a sensitive marker for beta-cell dysfunction. The objective of this study was to assess the proinsulin profile in persons with insulin-dependent diabetes mellitus (IDDM) after pancreas-kidney transplantation. We determined serum insulin, C-peptide, and proinsulin concentrations during an oral glucose challenge in five pancreas-kidney transplant recipients, nine nondiabetic kidney transplant recipients, and 17 normal subjects. Basal proinsulin concentrations were significantly increased in pancreas-kidney recipients (geometric mean [+/-1 SE range], 6.0 [5.5 to 6.4] pmol/L) and kidney recipients (6.4 [5.4 to 7.5] pmol/L) compared with the normal subjects (2.8 [2.5 to 3.2] pmol/L). Integrated proinsulin concentrations during the oral glucose load were also higher in pancreas-kidney recipients (1.4 [1.1 to 1.8] nmol/L x min) and kidney recipients (1.5 [1.2 to 2.0] nmol/L x min) versus normal subjects (0.8 [0.7 to 0.9] nmol/L x min). There was no difference in basal or integrated proinsulin concentrations between the two transplant groups. Even after adjustment for the glomerular filtration rate (GFR), basal and incremental proinsulin concentrations continued to be higher in the transplant groups than in the normal subjects. Proinsulin to C-peptide molar ratios both before and after the glucose load were similar in the three groups. From these findings, we conclude that pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with its reduced clearance in the kidneys.

Adult↗
PubMed1999

T-cell response to proinsulin and insulin in type 1 and pretype 1 diabetes.

Insulin-dependent diabetes mellitus (IDDM) results from the selective destruction of pancreatic beta cells by a T cell-mediated autoimmune process. Insulin and proinsulin are the only known beta cell-specific autoantigens. Using short-term cultures of freshly isolated peripheral blood mononuclear cells, we evaluated T-cell responses to proinsulin and to insulin in IDDM patients and individuals at risk for IDDM. A proliferative T-cell response to proinsulin was observed in only 2 of 26 recent-onset IDDM subjects and 2 of 12 long-standing IDDM subjects and was associated with a proliferative response to insulin. In contrast, 5 of 13 islet cell autoantibody-positive first-degree relatives of IDDM patients showed a proliferative response to proinsulin alone, 3 of 13 to insulin alone, and 1 of 13 to both insulin and proinsulin. Overall, 9 of 13 ICA-positive first-degree relatives responded to either proinsulin or insulin. We observed an inverse relationship between antiinsulin antibodies and T-cell responses to insulin in ICA-positive first-degree relatives but not in long-standing IDDM patients. Our data indicate that proinsulin is a major antigen in IDDM and, further, illustrate the difference between the autoimmune response to insulin and the immune response to exogenous insulin.

Adolescent↗
PubMed1995

Sequence requirements for proinsulin processing at the B-chain/C-peptide junction.

Proinsulin is converted into insulin by the action of two endoproteases. Type I (PC1/PC3) is thought to cleave between the B-chain and the connecting peptide (C-peptide) and type II (PC2) between the C-peptide and the A-chain. An acidic region immediately C-terminal to the point of cleavage at the B-chain/C-peptide junction is well conserved throughout evolution and has been suggested to be important for proinsulin conversion [Gross, Villa-Komaroff, Kahn, Weir and Halban (1989) J. Biol. Chem. 264, 21486-21490]. We have here compared the precise role of this region as a whole and just the first acidic residue C-terminal to the point of cleavage in processing of proinsulin by PC3. To this end, several mutations were introduced in this region of human proinsulin (native sequence, B-chain RREAEDL C-peptide): RRPAEDL (C1Pro mutant); RRLAEDL (C1Leu mutant); RRL (C1-C4del mutant); RRE (del-C1Glu mutant). Mutant and native cDNAs were stably transfected into AtT20 (pituitary corticotroph) cells, in which PC3 is known to be the major conversion endoprotease, and kinetics of proinsulin conversion were studied (pulse-chase/HPLC analysis of proinsulin-related peptides). The results show that the acidic region following the B-chain/C-peptide junction is indeed important for PC3 cleavage at this site, and that the reduced cleavage observed for the C1-C4del mutant proinsulin can be partially overcome by replacing the acidic region with a single acidic residue (del-C1Glu mutant). Replacing only the first residue of the acidic region with leucine (C1Leu mutant) has no impact on conversion, whereas its replacement with proline (C1Pro mutant) almost completely abolishes cleavage at the B-chain/C-peptide junction without affecting that at the C-peptide/A-chain junction.

Amino Acid Sequence↗
PubMed2001

Effect of insulin, proinsulin, and amylin on renin release from perfused rat kidney.

To evaluate the possible role of insulin, proinsulin, and amylin in the renin-angiotensin system, the direct effect of these peptides on renin release was examined using perfused kidney of rats. Renin release was significantly increased from a basal value of 6.1 +/- 1.8 to a peak value of 10.1 +/- 2.3 ng angiotensin I (Ang I)/mL/h by 0.5 nmol insulin, from 6.0 +/- 1.7 to 16.7 +/- 4.5 ng Ang I/mL/h by 1 nmol insulin, and from 6.1 +/- 1.8 to 18.0 +/- 5.5 ng Ang I/mL/h by 8 nmol insulin. Renin release was not significantly changed by perfusion of 0.05 nmol proinsulin or amylin but significantly increased from a basal value of 6.1 +/- 1.7 to a peak value of 8.1 +/- 3.6 ng Ang I/mL/h by 1 nmol proinsulin, from 5.6 +/- 1.7 to 12.1 +/- 3.8 ng Ang I/mL/h by 8 nmol proinsulin, from 5.7 +/- 1.9 to 8.2 +/- 3.5 ng Ang I/mL/h by 1 nmol amylin, and from 5.2 +/- 2.0 to 12.4 +/- 3.3 ng Ang I/mL/h by 8 nmol amylin. The concentration of cyclic adenosine monophosphate in the effluent was significantly increased from a basal value of 5.1 +/- 1.6 to a peak value of 10.6 +/- 2.5 mmol/min by 8 nmol amylin but not altered by perfusion of insulin or proinsulin. The addition of 0.05 nmol proinsulin and 0.05 nmol of amylin on 0.5 nmol insulin significantly enhanced renin release. These results indicate that insulin may play an important physiologic role in the renin-angiotensin system and suggest that proinsulin and amylin may be involved in the genesis and development of hypertension through enhancement of insulin-stimulated renin release.

Amyloid↗
PubMed1989

Measurement of proinsulin in human pancreatic juice.

In this study, we measured proinsulin in human pancreatic juice by radioimmunoassay (RIA). Affinity chromatography was used to separate proinsulin and insulin from C-peptide; and high-performance liquid chromatography, to separate proinsulin from insulin. In the RIA procedure for proinsulin we used porcine insulin antiserum as the antibody and porcine proinsulin as the standard and labelled antigen. The concentrations of proinsulin in human pancreatic juice obtained 5, 10, 15 and 20 minutes after intravenous injection of secretin were 29 +/- 6, 41 +/- 4, 35 +/- 14 and 37 +/- 17 (pmol/l +/- SD, means of 7 subjects), respectively. These values were higher than those in serum from fasted subjects, 12 +/- 4 pmol +/- SD. This work shows that proinsulin is present in human pancreatic juice.

Adolescent↗