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  • 1
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 248 (1974), S. 151-152 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] FIG. 1 Assignment of the primary structure of guinea pig C-peptide. The horizontal arrows indicate the peptides liberated by the action of chymotrypsin (Chy) or cyanogen bromide (C) on the intact C-peptide and by the action of papain on the resulting fragments. The half arrows indicate amino acids ...
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Insulin analogues ; albumin binding ; prolonged action ; basal insulin ; fatty acids ; tetradecanoic acid ; myristic acid ; lysineB29 ; acylation ; receptor affinity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have synthesized insulins acylated by fatty acids in the ε-amino group of LysB29. Soluble preparations can be made in the usual concentration of 600 nmol/ml (100 IU/ml) at neutral pH. The time for 50% disappearance after subcutaneous injection of the corresponding TyrA14(125I)-labelled insulins in pigs correlated with the affinity for binding to albumin (r=0.97), suggesting that the mechanism of prolonged disappearance is binding to albumin in subcutis. Most protracted was LysB29-tetradecanoyl des-(B30) insulin. The time for 50% disappearance was 14.3±2.2 h, significantly longer than that of Neutral Protamine Hagedorn (NPH) insulin, 10.5±4.3 h (p〈0.001), and with less inter-pig variation (p〈0.001). Intravenous bolus injections of LysB29-tetradecanoyl des-(B30) human insulin showed a protracted blood glucose lowering effect compared to that of human insulin. The relative affinity of LysB29-tetradecanoyl des-(B30) insulin to the insulin receptor is 46%. In a 24-h glucose clamp study in pigs the total glucose consumptions for LysB29-tetradecanoyl des-(B30) insulin and NPH were not significantly different (p=0.88), whereas the times when 50% of the total glucose had been infused were significantly different, 7.9±1.0 h and 6.2±1.3 h, respectively (p〈0.04). The glucose disposal curve caused by LysB29-tetradecanoyl des-(B30) insulin was more steady than that caused by NPH, without the pronounced peak at 3 h. Unlike the crystalline insulins, the soluble LysB29-tetradecanoyl des-(B30) insulin does not elicit invasion of macrophages at the site of injection. Thus, LysB29-tetradecanoyl des-(B30) insulin might be suitable for providing basal insulin in the treatment of diabetes mellitus.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Intestine ; insulin-releasing factor ; GLI ; islets ; pancreas pieces
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Des extraits à l'acide éthanol ont été préparés à partir du coeur, duodénum, ileum + jejunum (TOT) du porc et TOT fractionnée sur colonne chromato-graphique. Avec les ilôts du rat et les morceaux de pancréas du rat, incubés dans du glucose 16.6 mM, on a déterminé pour chaque produit son activité insulinolibératrice (IRA). Les extraits de coeur et duodénum n'accrurent pas la libération d'insuline; le glucagon pancréatique et TOT l'augmentèrent significativement. La secrétine synthétique n'agit point sur la libération d'insuline, par les ilôts isolés, mais la pancréozymine très faiblement. La production d'insuline, par les ilôts et les morceaux, fut stimulée par quelques fractions de TOT, les effets dépendant des concentrations des fractions entre 5 et 250 μg/ml. Les contenus en GLI, pancréozymine et secrétine de ces produits furent comparés avec leurs IRAs. L'IRA, rapporté ici, n'est pas du à la secrétine, ni probablement à la pancréozymine. Il n'existe pas de relations quantitatives entre le GLI et IRA des fractions.
    Abstract: Zusammenfassung Säureäthanolextrakte wurden aus dem Ileum + Jejunum (TOT), Herz und Duodenum des Schweins zubereitet. TOT wurde mittels Säulenchromatographie fraktioniert. Die insulinfreisetzende Aktivität (IRA) dieser Stoffe wurde an Ratteninseln und Rattenpankreasstückchen bestimmt, die mit 16.6 mM Glucose inkubiert worden waren. Die Herz- und Duodenumextrakte hatten keine Wirkung auf die Insulinausschüttung. Pankreasglucagon und TOT bewirkten eine signifikante Erhöhung der Insulinfreigabe. Synthetisches Sekretin bewirkte keine Erhöhung der Insulinfreisetzung aus isolierten Inseln. Pancreozymin hatte nur eine geringe Wirkung auf die Insulinproduktion der Inseln. Einige der Fraktionen von TOT erhöhten die Insulinproduktion der Inseln und der Pankreasstückchen. Im Konzentrations-bereich von 5 – 250 μg/ml waren die Wirkungen dieser Fraktionen konzentrationsabhängig. Der GLI-, Pancreozymin- und Sekretingehalt dieser Stoffe wird mit ihren IRAs verglichen. Die hier beschriebene IRA wird nicht durch Sekretin verursacht, wahrscheinlich auch nicht durch Pancreozymin. Es besteht keine quantitative Wechselbeziehung zwischen der GLI und der IRA der Fraktionen.
    Notes: Summary Acid-ethanol extracts were prepared from pork ileum + jejunum (TOT), heart and duodenum. TOT was fractionated by column chromatography. The insulin-releasing activities (IRA) of these materials were determined using rat islets and pieces of rat pancreas incubated with 16.6 mM glucose. The heart and duodenum extracts were without effect on insulin release. Pancreatic flucagon and TOT significantly increased insulin release. Synthetic secretin did not increase insulin release by isolated islets. Pancreozymin had only slight effects on the insulin output by islets. Some of the fractions of TOT increased the insulin output of islets and pancreas pices. The effects of these fractions were concentration-dependent in the range 5 to 250 μ/ml. The contents of GLI, pancreozymin and secretin in these materials are compared with their IRAs. The IRA described here is not caused by secretin, and is probably not caused by pancreozymin. There is no quantitative correlation between the GLI and the IRA of the fractions.
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords Insulin analogues ; albumin binding ; prolonged action ; basal insulin ; fatty acids ; tetradecanoic acid ; myristic acid ; lysineB29 ; acylation ; receptor affinity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have synthesized insulins acylated by fatty acids in the ɛ-amino group of LysB29. Soluble preparations can be made in the usual concentration of 600 nmol/ml (100 IU/ml) at neutral pH. The time for 50 % disappearance after subcutaneous injection of the corresponding TyrA14(125I)-labelled insulins in pigs correlated with the affinity for binding to albumin (r = 0.97), suggesting that the mechanism of prolonged disappearance is binding to albumin in subcutis. Most protracted was LysB29-tetradecanoyl des-(B30) insulin. The time for 50 % disappearance was 14.3 ± 2.2 h, significantly longer than that of Neutral Protamine Hagedorn (NPH) insulin, 10.5 ± 4.3 h (p 〈 0.001), and with less inter-pig variation (p 〈 0.001). Intravenous bolus injections of LysB29-tetradecanoyl des-(B30) human insulin showed a protracted blood glucose lowering effect compared to that of human insulin. The relative affinity of LysB29-tetradecanoyl des-(B30) insulin to the insulin receptor is 46 %. In a 24-h glucose clamp study in pigs the total glucose consumptions for LysB29-tetradecanoyl des-(B30) insulin and NPH were not significantly different (p = 0.88), whereas the times when 50 % of the total glucose had been infused were significantly different, 7.9 ± 1.0 h and 6.2 ± 1.3 h, respectively (p 〈 0.04). The glucose disposal curve caused by LysB29-tetradecanoyl des-(B30) insulin was more steady than that caused by NPH, without the pronounced peak at 3 h. Unlike the crystalline insulins, the soluble LysB29-tetradecanoyl des-(B30) insulin does not elicit invasion of macrophages at the site of injection. Thus, LysB29-tetradecanoyl des-(B30) insulin might be suitable for providing basal insulin in the treatment of diabetes mellitus. [Diabetologia (1996) 39: 281–288]
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Fatty acid acylated insulin ; glucose turnover ; hindlimb lymph ; transendothelial transport ; albumin binding.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p 〈 0.001) and increased in interstitial fluid (163 ± 14 vs 106 ± 9 pmol/l, p 〈 0.01). The halftime for appearance of NN304 in interstitial fluid was slower than human insulin (92 vs 29 min, p 〈 0.001). Yet, equivalency of action was shown for glucose turnover; steady-state glucose uptake (Rd) of 7.28 ± 0.55 and 6.76 ± 0.24 mg · min–1· kg–1 and endogenous glucose production of 0.11 ± 0.12 and 0.22 ± 0.03 mg · min–1· kg–1 (p 〉 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p 〈 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263]
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