Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs
✍ Scribed by J. Markussen; S. Havelund; P. Kurtzhals; A. S. Andersen; J. Halstrøm; E. Hasselager; U. D. Larsen; U. Ribel; L. Schäffer; K. Vad; I. Jonassen
- Book ID
- 104767325
- Publisher
- Springer
- Year
- 1996
- Tongue
- English
- Weight
- 932 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0012-186X
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✦ Synopsis
We have synthesized insulins acylated by fatty acids in the e-amino group of Lys B29. 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(1;sI)-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_+4.3h (p < 0.001), and with less inter-pig variation (p < 0.001). Intravenous bolus injections of Lys Bz9tetradecanoyl des-(B30) human insulin showed a protracted blood glucose lowering effect compared to that of human insulin. The relative affinity of Lys B29tetradecanoyl 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 LysB;9-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]