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PubMed2002

Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study.

AIMS/HYPOTHESIS: Higher concentrations of insulin correlate with several coronary heart disease (CHD) risk factors and have been shown to predict incident CHD in several studies, leading to hypotheses concerning the proatherogenic properties of insulin. However, in cross-sectional studies, relationships of concentrations of the insulin precursor molecules, proinsulin and des 31, 32 proinsulin, relate as strongly, or more strongly, to levels of risk factors and to (prevalent) CHD. METHODS: We investigated the relationship between concentrations of insulin, measured with a specific assay, and of proinsulin-like molecules, and risk factors in 1181 non-diabetic men 50-64 years old during Phase II of the Caerphilly Study. We also related concentrations of these molecules to incident CHD during the 10-14 years follow-up. RESULTS: The relationship between concentrations of insulin, of proinsulin and of des 31, 32 proinsulin and BMI ( r = 0.36-0.45), triglyceride (r = 0.25-0.31), high density lipoprotein- (HDL-) cholesterol (r = -0.17 to -0.21), systolic ( r = 0.05-0.11) and diastolic blood pressure ( r = 0.11-0.15) were similarly close, those with risk factors being somewhat and similarly reduced after adjustment for BMI. The correlation between insulin and of proinsulin-like molecules and those plasminogen activator inhibitor-1 (PAI-1) antigen was also similar (r = 0.28-0.29). There was a negative correlation between concentrations of proinsulin-like molecules - but not insulin - and birth weight. Insulin concentrations correlated positively with height ( r = 0.12). In logistic regression models, concentrations of proinsulin-like molecules, but not insulin, predicted incident of CHD over a follow-up of 10-14 years (insulin - standardised odds ratio (SOR) 1.30 (95 %-CI) 0.91, 1.85), p = 0.15; des 31, 32 proinsulin - SOR 1.38 (95 %-CI 1.02, 1.85), p = 0.034; sum of proinsulin-like molecules - SOR 1.54 (95 %-CI 1.07, 2.20), p = 0.019 after adjusting for age and BMI. The predictive ability of these molecules was reduced by around one third after adjustment for standard risk factors and concentrations of tryglyceride and HDL-cholesterol, and by about half after further adjustment for PAI-1 concentrations. CONCLUSION/INTERPRETATION: We conclude that concentrations of proinsulin-like molecules provide a better way to predict the incidence of CHD than those of insulin. However, the lack of biological evidence for a causative relationship suggests an association through a common antecedent, and this antecedent is not likely to be intrauterine growth retardation.

Biomarkers↗
PubMed1981

Degradation of proinsulin and isolated C-peptide by rat kidney neutral metallo-endopeptidase.

Previous studies have shown that a neutral metallo-endopeptidase purified from rat kidney degrades the B chain of insulin, glucagon, ACTH and, at a markedly slower rate, the A chain of insulin. In contrast the enzyme does not attack native insulin, oxytocin, vasopressin, ribonuclease, albumin or denatured hemoglobin. The current studies demonstrate that the neutral peptidase also degrades the isolated C-peptide of proinsulin and cleaves certain peptide bonds in and near the C-peptide moiety of native proinsulin. Time courses of the formation of fluorescamine-reactive material during digestion of proinsulin and isolated C-peptide with the peptidase were identical. However, structural analysis of the peptidase-digested proinsulin showed that the enzyme does not convert proinsulin to insulin but that the peptidase cleaves one bond, Tyr26-Thr27, in the B chain moiety and five bonds in the C-peptide moiety, producing four split proinsulins. One of the split proinsulins is des-octacosa-peptide (27-54) porcine proinsulin or des-tetracosapeptide (27-50) bovine proinsulin. Each is a derivative of the insulin molecule having an extension of nine residues (ten residues in the case of the derivative from bovine proinsulin) at the N-terminus of A chain and lacking four residues at the C-terminus of B chain. This two chain derivative retains full immunoreactivity with insulin antibodies and exhibits 2.4-times more biological activity (promotion of glycogenesis in primary cultured hepatocytes) than proinsulin and about two-thirds the activity of insulin.

Amino Acid Sequence↗
PubMedDate not supplied

Circulating proinsulin-like molecules.

An improved understanding of the characteristics of proinsulin and its intermediate conversion products has resulted from the use of novel assays for distinguishing these molecules from insulin. Use of such assays may help clarify the role of insulin deficiency in non-insulin-dependent diabetes mellitus (NIDDM). Levels of proinsulin-like molecules are elevated in subjects who have NIDDM or impaired glucose tolerance. However, the observation that hyperproinsulinemia may occur in individuals without hyperglycemia suggests that elevated proinsulin levels may be a manifestation of beta-cell dysfunction rather than of increased demand on the beta cell. Although the metabolic effects of proinsulin-like molecules have yet to be elucidated, some studies indicate that the effect of these molecules on hepatocytes is greater than that on other insulin-sensitive cells. A potential therapeutic role of proinsulin in NIDDM thus has been envisioned, in that suppression of hepatic glucose output might reduce the risk of hypoglycemia caused by increased peripheral glucose uptake. Clinical study of proinsulin has been discontinued, however, owing to the finding of an association between use of human proinsulin and cardiovascular adverse events in one study. In NIDDM subjects, associations have been reported between elevated des 31,32 proinsulin concentrations and such cardiovascular risk factors as elevated blood pressure, increased serum triglyceride and total cholesterol values, and elevated plasminogen-activator inhibitor levels, suggesting a role of proinsulin in cardiovascular risk. Epidemiologic data, however, indicate that elevated levels of proinsulin-like molecules are related to low birth weight and that low birth weight is associated with increased risk of cardiovascular events, suggesting that inadequate intrauterine nutrition may be the common antecedent of augmented proinsulin levels and cardiovascular risk.

Amino Acid Sequence↗
PubMed1980

Translational control of proinsulin synthesis by glucose.

Glucose is known to stimulate proinsulin synthesis in pancreatic islets of rats as well as of many other animals, but the mechanism involved remains uncertain. If proinsulin induction by glucose is regulated at the transcriptional level, the amount of proinsulin mRNA may be increased by the administration of glucose. Alternatively, if proinsulin induction is regulated at the translational level, the rate of proinsulin synthesis may not be correlated with the amount of proinsulin mRNA. We have now used a proinsulin cDNA hybridisation method to determine the amount of proinsulin mRNA and the subcellular distribuation of proinsulin mRNA in rat pancreatic islets. The results suggest that glucose-induced proinsulin synthesis is mainly achieved by enhancing the trnaslation efficiency of proinsulin mRNA preexistent on the membrane-bound polysome in pancreatic islets.

Animals↗
PubMed2026

Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.

Altered proinsulin levels in β-cells and bloodstream are hallmarks of diabetes and other diseases, but our knowledge about the proinsulin regulators remains limited. Here we perform a genome-wide CRISPR screen to identify 84 proinsulin regulators that alter intracellular proinsulin/insulin ratio in a mouse β-cell line. The proinsulin regulators are distinct from the insulin regulators from a previous orthogonal CRISPR screen. Functional annotation of the proinsulin regulators highlights Golgi as the primary organelle for proinsulin storage and regulation. Trafficking towards the Golgi increases the intra-cellular proinsulin/insulin ratio, while trafficking away from the Golgi, including exocytosis and Golgi-to-ER retrograde transport, decreases the intracellular proinsulin levels. We also map mouse quantitative trait loci (QTLs) associated with plasma proinsulin levels and use the CRISPR screen results to pinpoint the causal genes within the QTL loci. Interestingly, protein disulfide isomerase Pdia6 is the strongest hit from both CRISPR screen and the in vivo QTL mapping. Knocking down Pdia6 significantly reduce proinsulin accumulation in Golgi and secretory granules. Intriguingly, Pdia6-depletion in both human and mouse β-cells does not affect the folding status of proinsulin but causes significantly impaired proinsulin production through a UPR-independent mechanism. Taken together, our genetic profiles provide mechanistic insights into the regulation of proinsulin/insulin homeostasis.

Animals↗
PubMed2005

The selective recruitment of mRNA to the ER and an increase in initiation are important for glucose-stimulated proinsulin synthesis in pancreatic beta-cells.

Glucose acutely stimulates proinsulin synthesis in pancreatic beta-cells through a poorly understood post-transcriptional mechanism. In the present study, we demonstrate in pancreatic beta-cells that glucose stimulates the recruitment of ribosome-associated proinsulin mRNA, located in the cytoplasm, to the ER (endoplasmic reticulum), the site of proinsulin synthesis, and that this plays an important role in glucose-stimulated proinsulin synthesis. Interestingly, glucose has greater stimulatory effect on the recruitment of proinsulin mRNA to the ER compared with other mRNAs encoding secretory proteins. This, as far as we are aware, is the first example whereby mRNAs encoding secretory proteins are selectively recruited to the ER and provides a novel regulatory mechanism for secretory protein synthesis. Contrary to previous reports, and importantly in understanding the mechanism by which glucose stimulates proinsulin synthesis, we demonstrate that there is no large pool of 'free' proinsulin mRNA in the cytoplasm and that glucose does not increase the rate of de novo initiation on the proinsulin mRNA. However, we show that glucose does stimulate the rate of ribosome recruitment on to ribosome-associated proinsulin mRNA. In conclusion, our results provide evidence that the selective recruitment of proinsulin mRNA to the ER, together with increases in the rate of initiation are important mediators of glucose-stimulated proinsulin synthesis in pancreatic beta-cells.

Animals↗
PubMed1997

The role of insulin and proinsulin in the regulation of triglyceride metabolism.

The mechanisms underlying the associations between abnormal glucose tolerance and myocardial infarction are poorly understood. It has often been suggested that an increased plasma insulin concentration is causally linked to many of the metabolic abnormalities that are associated with abnormal glucose tolerance, although this suggestion remains controversial. Recently it has been proposed that proinsulin and proinsulin-like molecules may also be involved in the atherogenic process. Both hyperinsulinaemia and insulin resistance are associated with fasting hypertriglyceridaemia and both increased VLDL production and increased plasma triglyceride concentrations commonly occur in association with abnormal glucose tolerance and atheromatous vascular disease. In order to study the effects of insulin, proinsulin and proinsulin-like molecules on hepatic triglyceride secretion we have undertaken experiments in vitro using the liver cell line HepG2. In conjunction with these in vitro experiments we have also studied, in vivo, the associations between insulin, proinsulin, proinsulin-like molecules and plasma triglyceride concentrations in subjects with both normal and abnormal glucose tolerance. Our results in vitro show that proinsulin and proinsulin-like molecules have similar and not different effects to insulin but are less biologically active. In vivo, our results show that concentrations of insulin, proinsulin and proinsulin-like molecules per se are not an important determinant of plasma triglyceride concentrations. Both abnormal NEFA suppression during an oral glucose tolerance test and increased central adiposity are closely linked to poor glucose tolerance and are the most important determinants of plasma triglyceride concentrations. Taken together these results suggest that it is not insulin nor proinsulin concentrations per se that are causally linked to hypertriglyceridaemia. We suggest that abnormal NEFA suppression plays an important part in the increase in risk of vascular disease associated with insulin resistance.

Adult↗
PubMed1971

Proinsulin-like component of circulating insulin in the basal state and in patients and hamsters with islet cell tumors.

The proinsulin-like component comprised approximately 20% of total circulating basal immunoreactive insulin in 15 patients without islet cell tumors. 15 min after oral glucose, the concentration of the proinsulin-like component was unchanged and its percentage of the total immunoreactive insulin decreased with the acute release of the insulin component. By 2 hr after oral glucose, the concentration of the proinsulin-like component increased and the insulin component concentration decreased so that the percentage of the proinsulin-like component was essentially the same as in the basal state. In five patients with islet cell tumors and fasting hypoglycemia, basal proinsulin-like component ranged from 26 to 79% of the total immunoreactive insulin. While basal proinsulin-like component was higher in the islet cell tumor patients, the fluctuations after stimulation were qualitatively similar to the nontumor patients. Acute stimulation with glucose, tolbutamide, leucine, and streptozotocin mainly released the insulin component resulting in a fall in the per cent proinsulin-like component with a subsequent increase in percentage of this component as the total insulin concentration returns towards basal levels. Three islet-cell tumor patients with less than 46% proinsulin-like component had favorable therapeutic responses to diazoxide whereas one patient with over 80% proinsulin-like component was completely refractory. Syrian hamsters bearing islet cell tumors provided an excellent model for islet cell tumors in man. These animals have a high proportion of a proinsulin-like component in plasma; stimulation of tumor slices in vitro with tolbutamide and glucagon releases mainly the insulin component similar to the observations in man. These studies suggest that the mechanisms regulating the release of the proinsulin-like and of the insulin components are different.

Acromegaly↗
PubMed1984

The metabolic effects of biosynthetic human proinsulin in individuals with type I diabetes.

To assess the significance of deficiency of circulating proinsulin in patients with type I diabetes mellitus, we studied the metabolic effects of biosynthetic human proinsulin in 24 patients. After withdrawing insulin, an infusion of proinsulin to physiological plasma levels did not prevent elevations of plasma glucose or beta-hydroxybutyrate. During steady state infusions of insulin and proinsulin, 13.7 times the steady state plasma level of proinsulin compared to insulin was required to maintain euglycemia. This finding indicates that proinsulin is approximately 7.3% as biologically active as insulin on a molar basis in maintaining glucose control. The MCRs of insulin and proinsulin during these steady state infusions were 12.5 +/- 2.2 (+/- SEM) and 2.62 +/- 0.33 ml/kg X min, respectively. After maintaining euglycemia overnight with an infusion of insulin or proinsulin and then acutely stopping these infusions, the rise in plasma glucose after proinsulin was delayed significantly compared to insulin, consistent with proinsulin's slower clearance. Further studies are necessary to determine whether biosynthetic human proinsulin has a specific role in the treatment of diabetes.

Blood Glucose↗
PubMed1984

The effects of biosynthetic human proinsulin on carbohydrate metabolism.

Large quantities of biosynthetic human proinsulin have recently become available through recombinant DNA technology. Since the in vivo effects of human proinsulin have not been studied in man, we compared the dose-response relationship for stimulation of glucose disposal and suppression of hepatic glucose output by proinsulin and insulin. Ten normal subjects were studied using the euglycemic glucose clamp technique. The human proinsulin and insulin infusion rates were chosen to achieve steady-state proinsulin levels 10-fold higher than insulin levels on a molar basis, based on previous observations that porcine proinsulin has approximately 10% the potency of insulin. Proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 micrograms/m2/min were compared with insulin infusion rates of 0.63, 1.67, 5, and 10 micrograms/m2/min. Primed, continuous infusions of insulin yielded steady-state levels within 25 min, whereas proinsulin levels did not reach a steady state for 120-180 min. The metabolic clearance rate of insulin was 11-12 ml/kg/min at the lower infusion rates but fell to 8.4 ml/kg/min at the highest infusion rate. The metabolic clearance rate of proinsulin was 3.0-3.5 ml/kg/min at all infusion rates. Dose-response analysis demonstrated that proinsulin-mediated glucose disposal was approximately 8% that of insulin. In contrast, proinsulin-mediated suppression of hepatic glucose output was approximately 12% that seen with insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Regulation of ketogenesis, gluconeogenesis, and glycogen synthesis by insulin and proinsulin in rat hepatocyte monolayer cultures.

The metabolic actions of porcine insulin and biosynthetic human proinsulin on fatty acid and glucose metabolism were studied in rat hepatocytes cultured in monolayer for 24 h. Our aim was to establish whether proinsulin action in the liver is similar to insulin action and whether the relative potencies of the two hormones are the same for different metabolic processes. Proinsulin and insulin exerted a similar maximal inhibitory effect on ketone body formation from palmitate and on gluconeogenesis from pyruvate. The half-maximal effective concentration of proinsulin was 11-13 times that of insulin. The antiketogenic effects of insulin and proinsulin were associated with an increased glycerol 3-phosphate content and a decreased affinity of carnitine palmitoyltransferase for its substrate palmitoyl-CoA. When the basal rate of ketogenesis was increased with isobutyl methylxanthine, the half-maximal effective concentrations of both proinsulin and insulin were decreased, but the relative potency of the two hormones was unchanged. Proinsulin and insulin exerted similar maximal stimulatory effects on glycogen synthesis and on the activities of pyruvate kinase, glucose 6-phosphate dehydrogenase, phosphogluconate dehydrogenase, and malic enzyme. The half-maximal effective concentration of proinsulin was 10-30 times that of insulin. These findings are consistent with receptor binding studies on liver membranes that suggest that proinsulin interacts with insulin-specific and not proinsulin-specific receptors. Our findings also suggest that proinsulin action does not differ from insulin action at a postreceptor site.

Animals↗
PubMed1992

Stimulation by proinsulin of expression of plasminogen activator inhibitor type-I in endothelial cells.

In patients with non-insulin-dependent diabetes mellitus, concentrations in plasma of insulin and its precursors, proinsulin and split proinsulin, are increased. Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. In addition, inhibition of tyrosine kinase, which mediates many of the diverse effects of insulin and insulinlike growth factor I, did not attenuate the effect of proinsulin. These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus.

Animals↗
PubMed1997

Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. A population study.

OBJECTIVE: As high serum insulin predicts impaired fibrinolysis and proinsulin reacts in most conventional insulin assays, we hypothesized that proinsulin could link low fibrinolytic activity and hyperinsulinemic conditions. RESEARCH DESIGN AND METHODS: We explored the relationship between fibrinolysis and plasma fibrinogen on the one hand and specific insulin and proinsulin on the other, in a healthy population sample of 165 men and women, 25-74 years of age, from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Study. Specific insulin and proinsulin were measured by enzyme-linked immunosorbent assay. Partial correlation coefficients, adjusted for age and sex, were calculated. RESULTS: Plasma fibrinogen levels were related to insulin (r = 0.25, P < 0.01) and proinsulin (r = 0.29, P < 0.001), as was plasminogen activator inhibitor (PAI)-1 activity (r = 0.36 and r = 0.29, respectively; P < 0.001). Tissue Plasminogen activator (tPA) activity correlated inversely to insulin (r = 0.35, P < 0.001) and proinsulin (r = - 0.36, P < 0.001). In a multivariate analysis taking also smoking and anthropometric and metabolic measurements into account, fasting proinsulin was a significant predictor of high plasma fibrinogen level. Insulin and proinsulin levels were not related to tPA activity. High levels of postload insulin, triglycerides, and diastolic blood pressure, but not proinsulin, predicted high PAI-l activity. CONCLUSIONS: In a healthy population, the relationship previously described between high insulin levels and impaired fibrinolysis is not attributable to confounding from proinsulin. Elevated proinsulin levels are associated with high fibrinogen levels.

Adult↗
PubMed1992

(A-C-B) human proinsulin, a novel insulin agonist and intermediate in the synthesis of biosynthetic human insulin.

The hormone insulin is synthesized in the beta cell of the pancreas as the precursor, proinsulin, where the carboxyl terminus of the B-chain is connected to the amino terminus of the A-chain by a connecting or C-peptide. Proinsulin is a weak insulin agonist that possesses a longer in vivo half-life than does insulin. A form of proinsulin clipped at the Arg65-Gly66 bond has been shown to be more potent than the parent molecule with protracted in vivo activity, presumably as a result of freeing the amino terminal residue of the A-chain. To generate a more active proinsulin-like molecule, we have constructed an "inverted" proinsulin molecule where the carboxyl terminus of the A-chain is connected to the amino terminus of the B-chain by the C-peptide, leaving the critical Gly1 residue free. Transformation of Escherichia coli with a plasmid coding for A-C-B human proinsulin led to the stable production of the protein. By a process of cell disruption, sulfitolysis, anion-exchange chromatography, refolding, and reversed-phase high-performance liquid chromatography, two forms of the inverted proinsulin differing at their amino termini as Gly1 and Met0-Gly1 were identified and purified to homogeneity. Both proteins were shown by a number of analytical techniques to be of the inverted sequence, with insulin-like disulfide bonding. Biological analyses by in vitro techniques revealed A-C-B human proinsulin to be intermediate in potency when compared to human insulin and proinsulin. The time to maximal lowering of blood glucose in the fasted normal rat appeared comparable to that of proinsulin. Additionally, we were able to generate fully active, native insulin from A-C-B human proinsulin by proteolytic transformation. The results of this study lend themselves to the generation of novel insulin-like peptides while providing a simplified route to the biosynthetic production of insulin.

Amino Acid Sequence↗
PubMed1995

Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects--evidence against a modulating role for insulin.

Elevated concentrations of proinsulin-like molecules, other than insulin, may be associated with abnormalities of cardiovascular risk factors, promoting atherogenesis and thrombosis. Using specific assays we examined the relationship of levels of insulin, intact proinsulin and des-31,32 proinsulin to blood pressure, lipids, fibrinogen, factor VII and albumin excretion rate in 270 europids with normal glucose tolerance. After correcting for age and body mass index, fasting and 2-h insulin concentrations were significantly associated with those of total and LDL-cholesterol (r = 0.18-0.22), HDL-cholesterol (both r = -0.20) and triglycerides (r = 0.21 and 0.18), but not with blood pressure. Concentrations of intact and des-31,32 proinsulin showed significant associations with those of total and LDL-cholesterol (r = 0.20-0.23), HDL-cholesterol (r = -0.31 and -0.32) and triglycerides (r = 0.22 and 0.26). Fasting insulin and intact proinsulin concentrations were significantly associated with fibrinogen (r = -0.15 and 0.18). Concentrations of proinsulin-like molecules comprised less than 10% of all insulin-like molecules, and so were calculated not to influence previously described relationships between insulin concentrations and cardiovascular risk factors measured using non-specific assays. In multiple regression analyses des-31,32 proinsulin concentration was more strongly associated with those of HDL-cholesterol (negatively), LDL-cholesterol and triglycerides than fasting insulin concentrations, while intact proinsulin replaced insulin concentrations in their relationships with fibrinogen. Our results show correlations between dyslipidaemia and proinsulin-like molecules at concentrations at which biological, insulin-like, activity appears unlikely. We also show relationships between LDL-cholesterol and fibrinogen and the proinsulin-like molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non-insulin-dependent) diabetes mellitus.

A simple and sensitive human proinsulin radioimmunoassay system was developed using guinea pig anti-proinsulin serum, which cross-reacted neither with human insulin nor C-peptide. The recognition site of the antiserum seems to be located near the junction between the B chain and C-peptide. With this assay system, we studied the serum proinsulin concentration at fasting and after an oral 100 g glucose load in 25 healthy subjects, 21 subjects with impaired glucose tolerance and 40 patients with Type 2 (non-insulin-dependent) diabetes mellitus. At fasting, serum proinsulin was 5.8 +/- 3.3 pmol/l in normal subjects as compared to 9.5 +/- 6.9 pmol/l (p less than 0.05) in subjects with impaired glucose tolerance and 12.6 +/- 7.5 pmol/l (p less than 0.001) in diabetic patients. The molar ratio of proinsulin to insulin was also increased in subjects with impaired glucose tolerance or diabetes compared to control subjects. After a 100 g oral glucose load, serum proinsulin increased more slowly than insulin. The proinsulin response after an oral glucose load was augmented in subjects with impaired glucose tolerance and diabetes, while the insulin response decreased with the elevation of fasting plasma glucose. Diabetic patients with high fasting plasma glucose had a very poor insulin response, but the proinsulin response was similar to control subjects. There was a linear correlation between summed proinsulin values and summed insulin values, but the slope of the regression line was steeper in diabetic patients than in control subjects. There was a relative increase in serum proinsulin both in subjects with impaired glucose tolerance and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The effects of human proinsulin on glucose turnover and intermediary metabolism.

We compared the effects of human proinsulin and human insulin on glucose disposal, suppression of hepatic glucose production (HGP), and intermediary carbohydrate and lipid metabolism. Six young, lean, subjects underwent eight separate euglycemic clamps with low-dose intravenous (IV) infusions of insulin and proinsulin (four each). The insulin infusions gave steady-state levels of 0.08 +/- 0.004 (I1), 0.12 +/- 0.003 (I2), 0.18 +/- 0.07 (I3), and 0.25 +/- 0.06 nmol/L (I4). The proinsulin infusions were chosen to give steady-state levels approximately 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5% to 10% the biological potency of insulin. Steady-state proinsulin levels were 1.2 +/- 0.04 (P1), 2.8 +/- 0.07 (P2), 4.5 +/- 0.3 (P3), and 6.9 +/- 0.3 nmol/L (P4). HGP was suppressed equally by proinsulin and insulin at the four dose levels. Percentage elevation of glucose disposal was significantly increased during each of the insulin infusions compared with proinsulin: I1 107% +/- 4%, P1 87% +/- 4% (P = .03); I2 143% +/- 7%, P2 125% +/- 12% (P = .01); I3 238% +/- 38%, P3 173% +/- 22% (P = .03); I4 283% +/- 17%, P4 178% +/- 11% (P = .002). Dose-response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately 3.3% compared with insulin. The effectiveness of proinsulin in suppressing HGP was approximately 5% compared with insulin. Plasma nonesterified fatty acids, blood glycerol, and 3-hydroxybutyrate were suppressed by similar amounts during each of the four insulin and proinsulin doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Plasma proinsulin in recently diagnosed type 2 diabetes mellitus.

We measured levels of immunoreactive insulin (IRI) and proinsulin using a sensitive and specific immunoradiometric assay (IRMA), in non-obese recently diagnosed type 2 diabetic subjects. The proinsulin IRMA showed full cross reaction with intact proinsulin, des 31-32 proinsulin and des 64-65 proinsulin, but no reaction with insulin or C-peptide. In a group of 41 recently diagnosed non-obese Caucasian type 2 diabetic subjects (study group), mean fasting proinsulin levels were greater than that of 40 age and body mass index (BMI) matched controls (study group 17.4 +/- 2.0, controls 10.1 +/- 0.9 pmol-1, P < 0.001). Following a standard test meal, 30 and 60 min levels were not significantly different between groups but 90- and 120-min proinsulin levels were elevated in the study group. The maximum proinsulin to IRI ratio was 20% in the fasting state and did not differ between study and control groups. Proinsulin profiles were similar in subjects receiving oral hypoglycaemic agents and those on dietary treatment alone. Proinsulin did not correlate with indices of glycaemic control, total cholesterol, triglycerides or HDL cholesterol, but a relationship was observed with IRI before and after the meal. These results suggest that increased secretion of insulin precursors of low biological activity occurs in non obese recently diagnosed type 2 diabetic subjects under reasonably good glycaemic control; in such individuals the elevated levels of these precursors are approximately in proportion to the increase in IRI and are less than those reported in some previous studies.

Blood Glucose↗