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  • 1
    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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  • 2
    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]
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1435-1803
    Keywords: Frank-Starling ; mechanism ; heart failure ; normal donor hearts ; dilated cardio-myopathy ; heart transplantation ; skinned fibres
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The Frank-Starling-mechanism (FSM) was analyzed in isolated intact and skinned human left ventricular myocardium obtained from 11 heart transplantations (normal donor hearts (NDH), n=8; dilated cardiomyopathy (DCM), n=11). The new technique to utilize muscle strips from normal donor hearts which were actually implanted is described in detail. Methods I) In electrically stimulated left ventricular trabeculae (37°C, oxygenated Krebs-Henseleit solution, supramaximal, electrical stimulation, frequency 1 Hz) force development was analyzed as a function of muscle length (NDH=8; DCM=11). II) In an additional series left ventricular myocardium was demembranized (“skinned”) by Triton-X-100. At different sarcomere lengths and calcium concentrations corresponding to pCa values of 4.3, 5.5, and 8.0 force development was measured (DCM=11; NDH=9). Results I) Developed force increased up to an optimum as a function of muscle length in intact NDH- and DCM-myocardium. However, the relative increment of developed force after any length step was smaller in DCM than in NDH. Near “Lmax” (muscle length associated with maximum developed force) passive resting tension was considerably elevated in DCM, indicating significantly incresed diastolic stiffness II) In skinned left ventricular DCM- and NDH-myocardium developed force depended on sarcomere length with an optimum near 2.2 μm. However, a reduction of activator calcium concentration from pCa 4.3 to pCa 5.5 produces a smaller percent decline in force at short sarcomere lengths in DCM than it does in NDH. Conclusion the present study shows that except for diastolic stiffness and a smaller relative force increment after any, length step in DCM the Frank Starling mechanism is still present in isolated human left ventricular DCM-as in NDH-myocardium. The current study does not allow to decide whether in skinned myocardium the smaller percent decline in force after reduction of activator calcium concentrations in DCM is caused by an increased calcium sensitivity at short sarcomere lengths or decreased sensitivity at long sarcomere lengths.
    Type of Medium: Electronic Resource
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