Metabolic footprint of the GLP-1 receptor agonist liraglutide in adolescent transgenic pigs with impaired incretin function

S Renner; E Streckel; C Braun-Reichhart; W Römisch-Margl; C Prehn; J Adamski; E Wolf

doi:10.1055/s-0034-1375129

Diabetologie und Stoffwechsel, Table of Contents

Metabolic footprint of the GLP-1 receptor agonist liraglutide in adolescent transgenic pigs with impaired incretin function

S Renner ¹, E Streckel ¹, C Braun-Reichhart ¹, W Römisch-Margl ², C Prehn ³^,⁴, J Adamski ³^,⁴, E Wolf ¹^,⁵

¹Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
²Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Research Center for Environmental Health, Neuherberg, Munich, Germany
³Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
⁴Institute of Experimental Genetics, Life and Food Science Center Weihenstephan, Technische Universität München, Freising, Germany
⁵Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany

Abstract

Aim: Metabolites can be very sensitive markers for the evaluation of drug efficiency and safety. We analyzed changes in the metabolome of adolescent pre-diabetic pigs expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR^dn) after treatment with the GLP-1 receptor agonist liraglutide using a targeted metabolomics approach.

Methods: 2-month-old GIPR^dntransgenic pigs were treated with 0.6 mg – 1.8 mg liraglutide or placebo once daily for 90 days. Plasma samples from mixed meal oral glucose tolerance tests performed after 90 days of treatment (4 measurements) were chosen for metabolite quantification. Quantification was based on ESI-LC-MS/MS measurements using the AbsoluteIDQ ^TM p180 kit (BIOCRATES) including free carnitine, acylcarnitines, amino acids, biogenic amines, sum of hexoses, glycerophospholipids and sphingolipids. Data were statistically evaluated by analysis of variance.

Results: Liraglutide-treated pigs revealed distinctly reduced body weight (-31%) and food intake (mean reduction of 30%), improved glucose tolerance (mixed meal oral glucose tolerance test at the end of the treatment period) and insulin sensitivity (reduced HOMA-IR) while no increasing effect on beta cell mass could be detected compared to placebo treatment.

Out of 186 metabolites quantified 27 revealed a significant group effect (liraglutide vs. placebo, p ≤0.0001). Affected metabolites were distributed over all groups: acylcarnitines (6), amino acids (1), glycerophospholipids (18) and sphingolipids (2). Additionally, plasma concentration of 8 metabolites changed significantly during the course of the glucose tolerance test.

Conclusion: Our study revealed characteristic changes of plasma metabolite concentrations in liraglutide^-treated pigs, contributing to a more comprehensive understanding of metabolic effects of this drug.