Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs

Diabetologia. 1996 Mar;39(3):281-8. doi: 10.1007/BF00418343.


We have synthesized insulins acylated by fatty acids in the epsilon-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.

MeSH terms

  • Acylation
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Female
  • Glucose Clamp Technique
  • Humans
  • Insulin / analogs & derivatives*
  • Insulin / chemical synthesis
  • Insulin / metabolism
  • Insulin / pharmacology*
  • Iodine Radioisotopes
  • Kinetics
  • Lysine
  • Macrophages / drug effects
  • Macrophages / pathology
  • Macrophages / physiology
  • Metabolic Clearance Rate
  • Protein Binding
  • Receptor, Insulin / metabolism*
  • Serum Albumin / metabolism*
  • Skin / drug effects
  • Swine


  • Blood Glucose
  • Insulin
  • Iodine Radioisotopes
  • Serum Albumin
  • Receptor, Insulin
  • Lysine