title: Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition.
abstract: BACKGROUND
  The glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. However, efficacy and safety of liraglutide in adolescents has not been systematically investigated. Furthermore, possible pro-proliferative effects of GLP1R agonists on the endocrine and exocrine pancreas need to be further evaluated. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass.
  
  
  METHODS
  Two-month-old GIPR(dn) transgenic pigs were treated daily with liraglutide (0.6-1.2 mg per day) or placebo for 90 days. Glucose homeostasis was evaluated prior to and at the end of the treatment period by performing mixed meal and intravenous glucose tolerance tests (MMGTT and IVGTT). Finally animals were subjected to necropsy and quantitative-stereological analyses were performed for evaluation of alpha- and beta-cell mass, beta-cell proliferation as well as acinus-cell proliferation.
  
  
  RESULTS
  MMGTT at the end of the study revealed 23% smaller area under the curve (AUC) for glucose, a 36% smaller AUC insulin, and improved insulin sensitivity, while IVGTT showed a 15% smaller AUC glucose but unchanged AUC insulin in liraglutide- vs. placebo-treated animals. Liraglutide led to marked reductions in body weight gain (-31%) and food intake (-30%) compared to placebo treatment, associated with reduced phosphorylation of insulin receptor beta (INSRB)/insulin-like growth factor-1 receptor beta (IGF1RB) and protein kinase B (AKT) in skeletal muscle. Absolute alpha- and beta-cell mass was reduced in liraglutide-treated animals, but alpha- and beta-cell mass-to-body weight ratios were unchanged. Liraglutide neither stimulated beta-cell proliferation in the endocrine pancreas nor acinus-cell proliferation in the exocrine pancreas, excluding both beneficial and detrimental effects on the pig pancreas.
  
  
  CONCLUSIONS
  Although plasma liraglutide levels of adolescent transgenic pigs treated in our study were higher compared to human trials, pro-proliferative effects on the endocrine or exocrine pancreas or other liraglutide-related side-effects were not observed.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. e.streckel@gen.vetmed.uni-muenchen.de.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Streckel
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. c.braun@gen.vetmed.uni-muenchen.de.
authors.forename: Christina
authors.initials: C
authors.lastname: Braun-Reichhart
authors.affiliation: Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. herbach@patho.vetmed.uni-muenchen.de.
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. dahlhoff@lmb.uni-muenchen.de.
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. b.kessler@gen.vetmed.uni-muenchen.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. blutke@patho.vetmed.uni-muenchen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. a.baehr@gen.vetmed.uni-muenchen.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bähr
authors.affiliation: Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. N.Uebel@med.vetmed.uni-muenchen.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Übel
authors.affiliation: Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. m.eddicks@lmu.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eddicks
authors.affiliation: Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. Ritzmann@med.vetmed.uni-muenchen.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Ritzmann
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, Germany. krebs-st@lmb.uni-muenchen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Department of Internal Medicine II, Clinical Center of the LMU Munich, Campus Großhadern, Munich, Germany. burkhard.goeke@med.uni-muenchen.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, Germany. blum@genzentrum.lmu.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany. wanke@patho.vetmed.uni-muenchen.de.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. ewolf@lmb.uni-muenchen.de.|Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, Germany. ewolf@lmb.uni-muenchen.de.|Gene Center, LMU Munich, Feodor-Lynen-Str. 25, D-81377, Munich, Germany. ewolf@lmb.uni-muenchen.de.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. s.renner@gen.vetmed.uni-muenchen.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Renner
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005746:Gastric Emptying / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D000069450:Liraglutide / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011236:Prediabetic State / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D000069450:Liraglutide; D058570:TOR Serine-Threonine Kinases; D000097789:Glucagon-Like Peptide-1 Receptor Agonists