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  • 1
    ISSN: 1432-0428
    Keywords: Chemically-modified insulins ; insulin structure-function ; bioactivity and metabolism in vivo ; competitive antagonism ; hypoglycaemia ; non-esterified fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The biological properties of three covalently-linked insulin dimers were studied in greyhounds. Constant infusions showed that the plasma distribution kinetics were slower for the dimers than for insulin. The metabolic clearance rates of the three dimers (10.3±0.4, 8.8±0.5, 8.2±0.5 ml· min-1· kg-1; mean ± SEM) were significantly lower than that of insulin (19±0.8 ml · min-1 · kg-1), and their hypoglycaemic effects (11.2%, 3% and 0.3%) were markedly reduced compared with their lipogenic potencies in vitro (80%, 30% and 13%, respectively). A low dose infusion of insulin or an equipotent dose of one of the dimers significantly prolonged the effects of an insulin bolus on plasma glucose but not on non-esterified fatty acids. The apparent distribution space (106.4±11.9 ml/kg) and clearance rate (14.7±0.5 ml · min-1 · kg-1) of an insulin bolus were significantly reduced by one dimer (44.5±8.4 ml/ kg and 10.7±2.8ml·min-1·kg-1) but not by the equipotent insulin infusion (102.7±8.2ml/kg and 16.4±0.07ml· min-1 · kg-1). The apparent partial competitive antagonism of insulin by the dimers that has been reported in vitro can be observed in vivo, in that antagonism of insulin metabolism was directly demonstrated with one of the dimers.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Non insulin dependent diabetes ; sulphonylurea therapy ; chlorpropamide ; glibenclamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6+0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 18 (1980), S. 59-63 
    ISSN: 1432-0428
    Keywords: Radioimmunoassay ; chemically modified insulins ; insulin antiserum specificity ; in vivo biological activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The reactions between four insulin antisera and eighteen insulin derivatives with modifications at the A1, B1 and B29 positions have been studied using a standard double-antibody radioimmunoassay procedure. The derivatives studied had: a) single modifications at A1, B1 or B29; b) modifications at two sites with or without a crosslink between them; c) modifications at all three sites with or without a crosslink. Analysis of the results showed a clear difference in the reactivity of the antisera. One antiserum (GP 5) was highly sensitive to modifications of the B1 residue and another (Ab 1) was sensitive to A1 and B29 modifications. Thus, immunological potencies of insulin analogues derived on the basis of these reactions with the antisera give widely varying results. These antisera were used in discriminatory radioimmunoassays of chemically modified insulins in biological fluids for estimation of in vivo hypoglycaemic potencies by an infusion technique, where the knowledge of the specificity of the antisera was useful in assessing the immunological identity of immunoreactive material in plasma with the analogue infused.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Dextrostix ; reflectance meter ; blood glucose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The useful range of blood glucose measurements with Dextrostix can be extended by varying the incubation time and making appropriate corrections to the observed values.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 20 (1981), S. 94-101 
    ISSN: 1432-0428
    Keywords: Chemically modified insulins ; gluconeogenesis ; glucose turnover ; insulin structure-function ; proinsulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A [14C]-glucose tracer infusion method was used to compare the effects of insulin infusion on glucose metabolism with the effects of infusion of three semisynthetic modified insulins and of proinsulin. Insulin produced hypoglycaemia in the anaesthetised dog by decreasing hepatic glucose production and increasing peripheral glucose utilisation. Compensatory antihypoglycaemic mechanisms eventually modified these responses. A1 B29-Diacetyl insulin exerted an hypoglycaemic effect entirely by stimulation of peripheral glucose uptake. A1-B29 crosslinked insulins and proinsulin produced hypoglycaemia almost entirely by decreasing hepatic glucose production and had little effect on tissue uptake. These observations suggest that insulin analogues may have actions in vivo that are qualitatively different from those of native insulin and suggest that certain analogues have a predominant action on the liver. This has important therapeutic implications concerning the development of semisynthetic insulins for clinical use.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Non insulin dependent diabetes ; sulphonylurea therapy ; chlorpropamide ; glibenclamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6±0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1041
    Keywords: propranolol ; practolol ; betaxolol ; hypoglycaemia ; free fatty acids ; glycerol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 1. Six healthy male volunteers received equivalent intravenous beta-blocking doses of propranolol, practolol and betaxolol (SL75212) or saline at weekly intervals Sixty minutes later 0.1 unit/kg insulin was given intravenously. 2. In all studies, maximum hypoglycaemia (mean 1.2 mmol/l) was reached thirty minutes after insulin. Recovery from hypoglycaemia was delayed with propranolol but practolol and betaxolol had no effect. 3. Propranolol blocked the tachycardia and widening of pulse pressure seen in saline treated subjects. It also blocked the rebound rise in free fatty acids (FFA) and glycerol concentrations that followed the nadir of hypoglycaemia. 4. Neither practolol nor betaxolol had significant effects on pulse rate or blood pressure but betaxolol resembled propranolol in blocking the rebound rise in FFA and glycerol, while practolol blocked the rise in glycerol alone. 5. The magnitude of the rise in growth hormone following hypoglycaemia was similar in all groups, but the peak was earlier after practolol and betaxolol.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 27 (1984), S. 207-211 
    ISSN: 1432-0428
    Keywords: Insulin binding ; insulin metabolism ; receptor ; compartmental analysis ; degradation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A simple model of the distribution and metabolism of insulin in vivo has been evaluated using data from insulin infusion into a group of normal subjects. The major rate-limiting step for access to degradation pathways is assumed to consist of binding of the ligand to a single population of insulin receptor sites, except that provision is made for the possibility of linear non-receptor-mediated degradation and for the phenomenon of negative cooperativity. The model has been shown to accommodate the non-linearity of insulin metabo lism, allows evaluation of receptor association and dissociation constants and provides for the first time an estimate of total accessible receptor number in the intact organism. For normal fasting man the model predicts 1.00±0.05 nmol accessible binding sites/kg (mean±SD).
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Bioscience reports 2 (1982), S. 785-793 
    ISSN: 1573-4935
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We have identified and isolated two forms of insulin receptor from rat-liver plasma membranes. The smaller (M r= 90k) is a single polypeptide. The same poly-peptide appears to be the insulin-binding site of the largerM r=280k). Only the larger, multisubunit, receptor shows high-affinity binding of insulin and negative cooperativity in its dissociation kinetics.
    Type of Medium: Electronic Resource
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