Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo

Abstract

Albumin is a multifunctional transport protein that binds a wide variety of endogenous substances and drugs. Insulins with affinity for albumin were engineered by acylation of the epsilon-amino group of LysB29 with saturated fatty acids containing 10-16 carbon atoms. The association constants for binding of the fatty acid acylated insulins to human albumin are in the order of 10(4)-10(5) M-1. The binding apparently involves both non-polar and ionic interactions with the protein. The acylated insulins bind at the long-chain fatty acid binding sites, but the binding affinity is lower than that of the free fatty acids and depends to a relatively small degree on the number of carbon atoms in the fatty acid chain. Differences in affinity of the acylated insulins for albumin are reflected in the relative timing of the blood-glucose-lowering effect after subcutaneous injection into rabbits. The acylated insulins provide a breakthrough in the search for soluble, prolonged-action insulin preparations for basal delivery of the hormone to the diabetic patient. We conclude that the biochemical concept of albumin binding can be applied to protract the effect of insulin, and suggest that derivatization with albumin-binding ligands could be generally applicable to prolong the action profile of peptide drugs.

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

“…Liraglutide has been reported to show an elimination half-life of 8.1 h [19]. This increase in the halflife of liraglutide is most likely to be mediated via a lower susceptibility to metabolism by DPP-IV [20] and a high degree of albumin binding of liraglutide (as has been shown for other fatty acid derivatives [21,22]); moreover, after subcutaneous administration, an additional prolongation of the half-life is mediated by slow absorption of liraglutide from the injection site, as evidenced by the further increase in half-life observed with subcutaneous vs intravenous administration. Thus, liraglutide treatment probably induces much higher plasma levels compared with native GLP-1 concentration in plasma [19,23,24].…”

Why mammals more susceptible to the hepatotoxic microcystins than fish: evidences from plasma and albumin protein binding through equilibrium dialysis

“…Among various plasma proteins, serum albumin is the predominant plasma protein, comprising more than half of the total protein in normal serum (Kanakis et al 2006;Ascoli et al 2006). It often contributes significantly towards the total binding of basic drugs in plasma (Kurtzhals et al 1995;Dennis et al 2002;Yuwiler et al 2006). So far as we have concerned, there is lack of report about the plasma protein binding of MC-RR and MC-LR as well as the specific binding of serum albumin across species.…”

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

“…Insulin detemir (NN304) (B29Lys(ε-tetradecanoyl),desB30 human insulin) is a soluble insulin analogue with a C 14 fatty acid side-chain at position B29 [4]. In the monomeric state, this side-chain binds to the fatty acid binding sites of albumin in plasma, developing equilibrium between free and albumin bound analogue [5]. Approximately 98% of detemir within the blood stream is bound to albumin [2,5].…”

“…In the monomeric state, this side-chain binds to the fatty acid binding sites of albumin in plasma, developing equilibrium between free and albumin bound analogue [5]. Approximately 98% of detemir within the blood stream is bound to albumin [2,5]. In contrast the prolongation of action of NPH insulin in the subcutaneous depot is dependent on non-covalent associations with zinc atoms and with protamine, such that after absorption into the circulation it exists in the free form identical to native human insulin [6].…”