title: Effects of gamma-glutamyl linker on DPP-IV resistance, duration of action and biological efficacy of acylated glucagon-like peptide-1.
abstract: Liraglutide, a GLP-1 mimetic has recently been approved for clinical use in obesity-diabetes. The purpose of this study was to assess if acylation of Liraglutide via its gamma-glutamyl linker contributes to DPP-IV inhibition and efficacy of the molecule, given that such an approach could be useful in prolonging bioactivity of related peptides. Liraglutide lacking the gamma-glutamyl linker (Lira-gammaGlu) and Liraglutide exhibited enhanced DPP-IV resistance with extension of t(1/2) plus effective cAMP production (EC(50): 0.15+/-0.11 and 0.16+/-0.11nM, respectively) compared to GLP-1 (EC(50) 3.81+/-0.80nM). GLP-1, Lira-gammaGlu and Liraglutide increased insulin secretion compared to glucose (1.5-3.0-fold; p<0.05 to p<0.001). In vivo, Lira-gammaGlu and Liraglutide significantly lowered plasma glucose when administered 4 and 8h prior to a glucose load (1.3-1.9-fold; p<0.05 to p<0.001). Twice-daily administration of Lira-gammaGlu and Liraglutide for 14 days significantly decreased food intake (1.2-fold; p<0.05) and plasma glucose (1.1-1.6-fold; p<0.05 to p<0.01) whilst increasing plasma insulin (1.4-1.6-fold; p<0.05). At 14 days, Lira-gammaGlu and Liraglutide markedly improved glucose tolerance (1.4-3.4-fold; p<0.05 to p<0.001), insulin response to glucose (1.4-1.5-fold; p<0.05), insulin sensitivity (1.3-1.4-fold; p<0.05 to p<0.01), as well as increasing pancreatic insulin content (1.4-fold; p<0.05). Functional characteristics of Lira-gammaGlu and Liraglutide are almost indistinguishable, questioning necessity of gamma-glutamyl linker in acylation for generation of long-acting incretin mimetics.
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kerr
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000215:Acylation / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D004351:Drug Resistance / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D018698:Glutamic Acid / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D013552:Swine; D016896:Treatment Outcome
chemical_list: D003432:Cross-Linking Reagents; D018698:Glutamic Acid; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4