Gene/Protein Disease Symptom Drug Enzyme Compound
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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperinsulinaemia is a reported feature of the inherited multisystem disorder myotonic dystrophy. This phenomenon has been attributed to a compensatory beta cell response to tissue insulin resistance. In this study, circulating concentrations of insulin, proinsulin, and split proinsulin molecules were determined after an overnight fast in ten patients with myotonic dystrophy using two-site monoclonal antibody-based immunoradiometric assays. Results were compared with ten healthy control subjects matched for age, gender, and body mass index. Oral glucose tolerance (75 g), as defined by World Health Organization criteria, was normal in all subjects. Fasting plasma immunoreactive insulin concentration, as determined using a conventional radioimmunoassay, was almost three times higher (p < 0.005) in the myotonic dystrophy patients than the healthy control subjects. By contrast, fasting concentrations (mean +/- SEM) of C-peptide (0.75 +/- 0.09 vs 0.52 +/- 0.03 nmol/l, p = 0.07) and immunoradiometrically-determined insulin (60 +/- 12 vs 38 +/- 4 pmol/l, p = 0.09) were not significantly different between the groups. Fasting concentrations of proinsulin (10.3 +/- 2.9 vs 1.6 +/- 0.3 pmol/l, p < 0.01), and 32-33 split proinsulin (7.8 +/- 2.5 vs 2.9 +/- 0.4 pmol/l, p < 0.05) were significantly elevated in the patients with myotonic dystrophy. Accordingly, the mean fasting proinsulin:insulin ratio, expressed as a percentage, was significantly increased in the myotonic patients (20 +/- 5 vs 4 +/- 1%, p < 0.01). The overall C-peptide response to the oral glucose challenge was significantly greater in the myotonic patients compared with the healthy control subjects (p < 0.001). These results provide corroborative evidence of increased beta-cell secretion in myotonic dystrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperproinsulinaemia in patients with myotonic dystrophy. 147 70

Three polymorphic sites of the apolipoprotein B gene - the insertion/deletion signal peptide, XbaI and EcoRI sites - were examined in a sample of 107 healthy men and in 46 men with evidence of coronary heart disease selected from a large population survey of South Asians aged 40-69 in London, U.K. There were no significant differences in allele frequencies between cases and controls. Frequencies of the ins (insertion) and X- (absence of XbaI cutting site) alleles were higher in South Asians than in Europeans studied previously (South Asians versus Europeans ins: 0.80 vs. 0.68, P less than 0.025; X-: 0.71 vs. 0.47-0.56, P less than 0.001). The del allele was associated with higher levels of total cholesterol (P less than 0.05) and the X+ allele with lower levels of HDL cholesterol (P less than 0.05), and thus both polymorphisms were associated with differences in the ratio of HDL cholesterol to total cholesterol (ins/del, P less than 0.01; XbaI, P less than 0.001). Mean waist-hip girth ratio was lower in the 10 men homozygous for the X+ allele than in the 42 men with X-/X+ and 55 men with X-/X- genotypes; the means (+/- SEM) were 0.92 +/- 0.02, 0.97 +/- 0.01 and 0.96 +/- 0.01 respectively (P = 0.03). These data suggest that genetic variation in linkage disequilibrium with the XbaI and ins/del polymorphisms of the apo B gene contributes to the determination of total cholesterol and HDL cholesterol levels and possibly to obesity in South Asians.
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PMID:Apolipoprotein B gene polymorphisms are associated with lipid levels in men of South Asian descent. 178 9

A highly specific two-site immunoradiometric assay for insulin was used to measure the plasma insulin response to 75 g glucose administered orally to 49 patients with non-insulin-dependent diabetes (NIDDM). The plasma insulin concentration 30 min after glucose ingestion was lower in the diabetic patients than in matched controls for both non-obese (11-83 pmol/l vs 136-297 pmol/l, p less than 0.01) and obese subjects (23-119 pmol/l vs 137-378 pmol/l, p less than 0.01). By means of another two-site immunoradiometric assay, the basal intact proinsulin level was found to be higher in the NIDDM patients than in the controls for both non-obese (7.1 [SEM 1.2] pmol/l vs 2.4 [0.4] pmol/l, p less than 0.01) and obese subjects (14.4 [2.2] pmol/l vs 5.9 [1.9] pmol/l, p less than 0.01). The basal level of 32-33 split proinsulin was also raised in NIDDM. Previous failure to show clear separation between normal and NIDDM insulin responses was probably due to the high concentrations of proinsulin-like molecules in the plasma of NIDDM patients. These substances cross-react as insulin in most, if not all, insulin radioimmunoassays but have very little biological insulin-like activity. It is therefore now possible and necessary to designate most NIDDM patients as insulin deficient.
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PMID:Insulin deficiency in non-insulin-dependent diabetes. 256 55

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.
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PMID:The effect of thyroid disease on proinsulin and C-peptide levels. 259 72

Twenty-one patients with evident lipoatrophy treated with conventional (Conv.) insulin were either allocated to continuation of treatment with previously used insulin (Conv. group, n = 10) or were transferred to Lente MC (monocomponent) insulin with or without supplementary Actrapid MC insulin (MC group, n = 11). On entry and after 3, 6 and 12 months of follow-up, serum insulin-, pancreatic polypeptide- and proinsulin-binding IgGs were determined by radioimmunoelectrophoresis according to the method of Christiansen. Prior to determination of proinsulin-binding IgG, the insulin-binding IgG was removed by means of sepharose-bound insulin according to the method of Heding. In both groups a slight decrease in the titer of insulin-binding IgG was observed: in the Conv. group from 5.33 +/- 0.92 (SEM) to 4.66 +/- 1.17 mU/ml after 12 months, and in the MC group from 3.22 +/- 0.64 to 2.66 +/- 0.46 mU/ml, respectively. Due to the small number of patients with pancreatic polypeptide antibody titers above the detection limit no statistical evaluation was carried out. The level of serum proinsulin-binding IgG decreased in the MC group only (from 9.3 +/- 2.2 to 1.9 +/- 0.6 ng/ml after 12 months), and even showed a slight increase in the Conv. group (the respective titers were: 14.0 +/- 4.6 and 14.9 +/- 4.6 ng/ml). In the MC group 10 patients (91%) showed improvement and 7 (64%) complete regression of their lipoatrophy corresponding to 6 (60%) and 2 (20%) in the Conv. group. This finding suggests a possible role of proinsulin-binding antibodies in the pathogenesis of insulin lipoatrophy.
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PMID:Controlled study comparing treatment with monocomponent insulin and conventional insulin in patients with lipoatrophy. 266 7

Counterregulatory effect following administration of biosynthetic human proinsulin (BHPI) and human insulin (BHI) were compared during hypoglycemia standardized by means of a glucose controlled insulin infusion system (GCIIS). A total of 0.148 +/- 0.010 U/kg of BHPI had to be given by the GCIIS in order to obtain a minimal blood glucose (BG) of 26 +/- 2 mg/dl (means +/- SEM) at 43 +/- 2 min. In contrast, 0.083 +/- 0.004 U/kg of BHI were sufficient to produce a minimal BG of 21 +/- 1 mg/dl (n.s.) at 35 +/- 1 min. (P less than 0.005). Moreover, BHPI infusion resulted in prolonged hypoglycemia and delayed blood glucose recovery. On a molar basis, the acute BG lowering effect of BHPI was about 13% that of BHI (BHPI 3.94 +/- 0.27 vs. BHI 0.51 +/- 0.03 nmol/kg). Serum proinsulin after BHPI reached its maximum of 19.4 +/- 2 pmol/ml at 20 min. and still exceeded basal values markedly at the end of the test period at 240 min. Serum insulin peaked at 10 min. (162 +/- 47 microU/ml) and had already returned to basal values (7.5 +/- 1 microU/ml) after 45 min. No severe side effects were observed and there was no need for glucose administration, but clinical symptoms of hypoglycemia were more pronounced after BHPI. Compared to BHI, BHPI produced a higher cortisol peak (252 +/- 16 vs. 168 +/- 10 ng/ml), a more pronounced secretion of ACTH and GH as well as a stronger decline of serum potassium (3.20 +/- 0.06 vs. 3.58 +/- 0.08 mmol/l). Counterregulatory prolactin secretion did not differ significantly. Urinary epinephrine secretion following hypoglycemia after BHPI exceeded that after BHI (10.3 +/- 4.8 vs. 3.0 +/- 0.5 ng/120 min.). Serum lactate increase after BHPI was more prolonged (1.68 +/- 0.24 vs. 0.37 +/- 0.14 mmol/l at 120 min.). BHPI-induced inhibition of lipolysis, as determined by free fatty acid patterns, was delayed and less pronounced. Our results indicate that the observed more distinct glucose counterregulation is due to prolonged hypoglycemia rather than to any specific BHPI action on the hypothalamic-pituitary axis. We regard this as a consequence of the prolonged circulating and biological half-life. A preferential proinsulin action on the liver may play an additional role. Whether this "depot effect" may be beneficial in the treatment of diabetes mellitus remains to be established.
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PMID:Comparative study of hormonal counterregulation during GCIIS-guided hypoglycemia tests using human proinsulin and human insulin (recombinant DNA). 284 67

To characterize the insulin-like growth factor I (IGF-I) receptor on human erythrocytes, cells were purified from peripheral blood by Ficoll-Hypaque gradient centrifugation and incubated with [125I]IGF-I. Specific binding was maximal at pH 8.0 after 24 h at 4 C and increased linearly with cell number to 3.9 +/- 0.2% (+/- SEM) for 3.0 X 10(9) cells/ml. The Scatchard plot of the binding data was linear, with 7 fmol [125I]IGF-I bound/10(9) cells and an affinity constant (K) of 1.8 X 10(9) M-1. Unlabeled IGF-I inhibited tracer binding half-maximally at 6 ng/ml. Multiplication-stimulating activity (or rat IGF-II) was 40% as potent (ED50, 15 ng/ml), whereas insulin and proinsulin were 30- to 500-fold less potent. A monoclonal antibody to the IGF-I receptor (alpha IR-3) inhibited IGF-I binding by 50% at a 1:1000 dilution and by 80% at a 1:250 dilution. Insulin binding was unaffected by the same dilutions. IGF-I receptor phosphorylation was studied in erythrocyte ghosts prepared by hypotonic lysis and solubilized in 1% Triton. The extract was preincubated with and without 100 ng/ml IGF-I or porcine insulin and incubated with [gamma-32P]ATP in the presence of Mn2+, and the receptor was identified by immunoprecipitation with alpha IR-3 antibody and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IGF-I stimulated 4-fold the incorporation of 32P into a protein of 95,000 mol wt, which was immunoprecipitated by alpha IR-3; insulin produced a 2-fold stimulation of this protein. This protein corresponds to the beta-subunit of the IGF-I receptor. These data demonstrate that human erythrocytes have specific receptors for IGF-I, and that this IGF-I receptor, like the insulin receptor, undergoes ligand-stimulated autophosphorylation. Thus, analysis of erythrocyte IGF-I binding and receptor phosphorylation may be useful tools for the study of patients with a variety of growth disorders.
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PMID:The human erythrocyte insulin-like growth factor I receptor: characterization and demonstration of ligand-stimulated autophosphorylation. 300 55

Thyrotropin-releasing hormone (TRH) and insulin were measured by radioimmunoassay in acetic-acid extracts of 19 pancreatic islet cell tumors induced by streptozotocin and nicotinamide in rats. In addition, gel filtration properties of TRH-immunoreactivity and immunoreactive insulin (IRI) were examined in 5 and 14 tumors, respectively. TRH was demonstrated in 10 of 19 tumors, with a mean of 166 +/- 47 (SEM) pg/mg wet weight, whereas the concentration was less than 3 pg/mg wet weight in the other tumors. In contrast, all tumors contained IRI, with a mean of 11.0 +/- 1.6 micrograms/mg wet weight. Ten tumors in which TRH was demonstrated contained more IRI than those in which TRH was not detected (13.1 +/- 1.8 vs 6.5 +/- 1.7 micrograms/mg wet weight, P less than 0.02). After gel filtration, all TRH immunoreactivity was eluted at the same place as synthetic TRH in the 5 tumors. In addition, gel filtration elutes showed essentially the same pattern of IRI in the 14 tumors, with 3 peaks. The predominant IRI peak comigrated with marker insulin (95.7 +/- 0.8%), another prominent peak occurred coincident with proinsulin standard (3.3 +/- 0.5%), a third peak was present in the void volume (0.28 +/- 0.04%). These distributions of IRI were similar to those in extracts of normal pancreases. The present studies demonstrate TRH immunoreactivity in pancreatic islet cell tumors induced by streptozotocin and nicotinamide in rats. Chemically induced insulinomas can serve as a model for insulin storage which is analogous to islet B cells.
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PMID:Thyrotropin-releasing hormone and insulin in chemically induced pancreatic islet cell tumors in rats. 302 23

Euglycaemic clamp experiments with single or combined infusions of human biosynthetic proinsulin and insulin were performed in 6 healthy, normal weight subjects in order to assess the possibility of antagonistic, additive, or synergistic effects on whole body glucose metabolism. Insulin (i: 2.02 pmol x kg-1 x min-1) or proinsulin (p: 9.26 pmol x kg-1 x min-1) were infused under euglycaemic clamp conditions over 240 min. After 120 min, the infusion rates were doubled (protocols ii and pp), or proinsulin (protocol ip) or insulin (protocol pi) infusions were added. After 240 min of infusing insulin or proinsulin alone, euglycaemia was maintained for an additional 60 min period without hormone infusions to measure the decay of hormone concentrations and of effects on glucose metabolism. Effects on glucose uptake were measured as the glucose infusion rate necessary to maintain euglycaemia. IR-insulin, IR-proinsulin, IR-C-peptide and IR-glucagon were determined by specific radioimmunoassays. After 240 min, similar steady state glucose infusion rates were reached for all protocols (mean +/- SEM, mg x kg-1 x min-1: ii: 10.6 +/- 1.0; ip: 9.1 +/- 0.4; pi: 10.0 +/- 0.9; pp: 8.4 +/- 0.7). The infusion rate with proinsulin alone (pp), however, was significantly smaller than with insulin alone (ii), indicating a somewhat lower effectiveness of the proinsulin dose employed. With all protocols, nonesterified fatty acid and IR-glucagon concentrations were decreased to a similar extent. Steady state hormone concentrations were reached within 30 min of each infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of single and combined infusions of human biosynthetic proinsulin and insulin on glucose metabolism and on plasma hormone concentrations in euglycaemic clamp experiments. 305 14

A radioimmunoassay, using an antiserum that is specific for human proinsulin, has been used to study the response of serum proinsulin to low (25 g) and high (75 g) oral glucose loads in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Diabetic patients were treated by diet only (N = 8) or were receiving oral anti-hyperglycemic agents (N = 8) and therapy was not interrupted during the study. In the fasted state, proinsulin concentrations were higher (P less than 0.05) in the drug-treated patients (31 +/- 3 pmol/l (SEM)) compared with age- and weight-matched healthy subjects (22 +/- 2 pmol/l; N = 10), but concentrations in the diet-treated patients 25 +/- 3 pmol/l) were not significantly different. Following 25 g and 75 g glucose loads, the rises in serum immunoreactive insulin and C-peptide concentrations in both groups of diabetic patients were impaired and delayed relative to those in the control subjects. The responses of serum proinsulin, however, were not significantly different in the NIDDM patients compared with controls at any time point up to 180 min except in the case of drug-treated patients receiving 25 g of glucose who had elevated (P less than 0.05) proinsulin concentrations at 150 min and 180 min after ingestion. It is concluded that NIDDM is not associated with an exaggerated release of proinsulin in response to glucose compared with healthy subjects, but the islets have maintained the ability to release proinsulin better than the ability to release insulin.
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PMID:Preferential release of proinsulin relative to insulin in non-insulin-dependent diabetes mellitus. 305 40


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