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  • 1
    ISSN: 1432-0428
    Keywords: Insulin analogues ; isolated fat cells ; biological potency ; lipogenesis ; inhibition of lipolysis ; combined biological action ; potentiation ; antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This paper presents a survey of the biological potencies of a variety of naturally-occurring and semi-synthetic insulin analogues and a study of the joint biological action of some of these materials with native insulin. Biological activity was tested on isolated rat fat cells using lipogenesis from glucose as the metabolic index. A brief comparison using inhibition of fat cell lipolysis was included. The results indicated: 1. Analogue potencies varied considerably (0.4–100% insulin activity). Values obtained were mainly confirmatory but included two further B1-modified materials and a tricarbamylated insulin. The results supported previous indications on the relative roles of the A1, B1, and B29 residues of insulin for hormone activity. 2. Analogue bioactivities, whether assessed by stimulation of lipogenesis or inhibition of lipolysis, were similar for the four materials tested in both systems. The response of fat cells with respect to both metabolic indices occurred over a comparable range of insulin concentrations, with half maximal effects at 30–35 pmol 1−1 insulin. 3. The presence of modified insulins appeared to alter the biological action of native insulinin vitro. Small effects of both potentiation and antagonism were identified.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Insulin structure-function ; chemically modified insulin ; proinsulin ; bioactivity of insulin analogues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Beef insulin, pork proinsulin and four derivatives of beef insulin modified at the A1-B29 site on the molecular surface have been studied. Three derivatives had a synthetic crosslink between the A and B chains. Previous studies with these materials [2, 3 and 5] had demonstrated in vivo bioactivities which were much higher than those displayed in vitro. This paper reports experiments which explain this discrepancy. The analogues were administered at equimolar rates to anaesthetised greyhounds by a priming-dose constant infusion technique and the plasma concentrations achieved were estimated by radioimmunoassay. Proinsulin and the modified insulins were metabolised more slowly than insulin. Biopotency values, which related fall in plasma glucose concentration to the total administered dose of analogue, agreed broadly with published results of conventional in vivo bioassays. On the other hand, calculation of potency in relation to the serum concentration of analogue actually achieved, yielded results which agreed more closely with in vitro assay data. We conclude that for these analogues, reported discrepancies between in vitro and in vivo biopotencies can be largely explained by the different rates at which these materials are metabolised.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 17 (1979), S. 331-331 
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    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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  • 5
    ISSN: 1432-0428
    Keywords: Iodoinsulin ; insulin metabolism ; insulin analogues ; biological activity ; tracer insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin, specifically substituted at the PheB1 position with 3,5-diiodotyrosine, has been tested in several biological and immunological systems. Immunoreactivity was assessed using antisera specific for different parts of the insulin molecule. Biological activity in vitro was estimated on isolated rat fat cells. In vivo bioactivity (hypoglycaemia) and metabolism (metabolic and urinary clearance rates, half-life, apparent distribution space) were measured by infusion of the material into greyhounds. The results indicated that this B1-labelled insulin preparation was biologically fully active and, unlike randomly labelled preparations of iodoinsulin, was metabolised with kinetics indistinguishable from those of the unlabelled hormone. We suggest that this material is a valid tracer for insulin, fulfilling the criteria of high specific activity and biological identity to the native hormone.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Il a été démontré que l'albumine peut prévenir mieux que la gélatine la perte d'insuline d'une solution contenant de l'insuline. Ceci a probablement conduit à des rapports erronés de taux d'ILA élevés dans les dosages avec des méthodes biologiques. Des préparations d'albumine humaine cristalline ne montraient ni d'ILA, ni d'insuline décelable par la méthode radio-immunologique. L'albumine humaine préparée après extraction par l'alcool-acide (qui dans des expériences antérieures a démontré des propriétés anti-insuliniques avec l'hémidiaphragme isolé du rat) montre une ILA considérable avec le tissu adipeux isolé du rat et aussi de l'insuline qui peut être démontrée par la méthode radioimmunologique.
    Abstract: Zusammenfassung Es konnte gezeigt werden, daß Albumin stärker als Gelatine den Insulinverlust insulin-haltiger Lösungen verhindern kann. Das hat wahrscheinlich zu falsch erhöhten Spiegeln der insulinähnlichen Aktivität (ILA) geführt, über die bei Bestimmung mit biologischen Methoden berichtet wurde. Präparate kristallinen menschlichen Albumins zeigten keine ILA und auch kein mit der radioimmunologischen Methode bestimmbares Insulin. Menschliches durch Säurealkohol-extraktion gewonnenes Albumin (das nach früheren Untersuchungen insulinantagonistische Eigenschaften am isolierten Rattenhemidiaphragma hat) zeigte am isolierten Rattenfettgewebe eine deutliche ILA und auch mit der radioimmunologischen Methode bestimmbares Insulin.
    Notes: Summary Albumin has been found to be more effective than gelatine in preventing insulin loss from insulin containing solutions. It is probable that this has led to falsely elevated levels of insulin-like activity (ILA) reported with bio-assays. Preparations of crystalline human albumin have been found to be free from ILA and from insulin measured by the radio-immuno-assay. Other human albumin prepared by acid-ethanol extraction (that has been shown previously to contain insulin antagonistic properties on the isolated rat hemidiaphragm) has contained significant ILA on the isolated rat fat pad and also contained insulin demonstrable by radio-immuno-assay.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 15 (1978), S. 29-32 
    ISSN: 1432-0428
    Keywords: Thyroxine ; triiodothyronine ; reverse T3 ; glucose utilization ; glucose metabolic clearance rate ; ketones ; oxygen consumption ; cortisol ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Thyroid hormones have been measured in normal subjects and insulin-requiring diabetic patients before and after treatment. Plasma thyroxine (T4) and 3, 3′, 5-triiodothyronine (T3) concentrations were both low in diabetics, with T3 frequently in the hypothyroid range, while 3, 3′, 5′-triiodothyronine (rT3) concentrations were elevated. All three returned to normal following treatment. T3 concentration was directly related to glucose utilization and metabolic clearance rate; and inversely related to plasma ketone body concentration. Thyroid hormone abnormalities in diabetes may reflect the degree of insulin-secreting capacity.
    Type of Medium: Electronic Resource
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  • 8
    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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  • 9
    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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  • 10
    ISSN: 1432-0428
    Keywords: Chronic (maturity onset) diabetes mellitus ; glucose tolerance ; insulin and growth hormone secretion ; intermediary metabolites ; lipids ; diet treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Thirty-five freshly presenting, diabetic patients received 5 hour, 100 g oral glucose tolerance tests when first seen and after a period of carbohydrate and energy restriction. After treatment, the significant improvement in glucose tolerance was accompanied by increased insulin secretion and lower concentrations of blood ketone bodies, lactate, glycerol, FFA, triglycerides, cholesterol and pre-beta lipoprotein. There were no significant changes in serum growth hormone or blood pyruvate concentrations. Improvement in glucose tolerance was greater in patients who were obese (〉115% of desirable body weight for height) on presentation and was related to the improvement in insulin secretion and the diminished lipolysis. An hypothesis to explain the changes in insulin secretion is proposed. Eleven out of the 35 patients showed sufficient improvement in glucose tolerance to require no treatment other than diet.
    Type of Medium: Electronic Resource
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