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-gamma Glu) and Liraglutide exhibited enhanced DPP-IV resistance with extension of t(1/2) plus effective cAMP production (EC50: 0.15 +/- 0.11 and 0.16 +/- 0.11 nM, respectively) compared to GLP-1 (EC50 3.81 +/- 0.80 nM). GLP-1, Lira-gamma Glu and Liraglutide increased insulin secretion compared to glucose (1.5-3.0-fold; p < 0.05 to p < 0.001). In vivo, Lira-gamma Glu and Liraglutide significantly lowered plasma glucose when administered 4 and 8 h prior to a glucose load (1.3-1.9-fold; p <0.05 top < 0.001). Twice-daily administration of Lira-gamma Glu 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-gamma Glu and Liraglutide markedly improved glucose tolerance (1.4-3.4-fold; p < 0.05 to p < 0.001), insulin response to glucose (1.41.5-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-gamma Glu and Liraglutide are almost indistinguishable, questioning necessity of gamma-glutamyl linker in acylation for generation of long-acting incretin mimetics. (C) 2010 Elsevier Inc. All rights reserved.