title: GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation.
abstract: Liraglutide and exenatide are glucagon-like peptide receptor (GLP-1R) agonists used in the treatment of type 2 diabetes. Both molecules have been associated with the development of thyroid C-cell tumors after lifetime exposure in rodents. Previously, it has been reported that these tumors are preceded by increased plasma calcitonin and C-cell hyperplasia. We can now document that the murine C-cell effects are mediated via GLP-1R. Thus, 13 wk of continuous exposure to GLP-1R agonists was associated with marked increases in plasma calcitonin and in the incidence of C-cell hyperplasia in wild-type mice. In contrast, similar effects were not seen in GLP-1R knockout mice. Human C-cell cancer is often caused by activating mutations in the rearranged-during-transfection (RET) protooncogene. We developed an immunohistochemical method to assess RET activation in tissues. Liraglutide dosing to mice was not found to activate RET. Further evaluation of the signaling pathways demonstrated that liraglutide increased ribosomal S6, but not MAPK kinase, phosphorylation. These observations are consistent with effects of GLP-1R agonists on rodent C cells being mediated via mammalian target of rapamycin activation in a RET- and MAPK-independent manner.
authors.affiliation: Novo Nordisk A/S, Novo Allé, DK-2880, Bagsvaerd, Denmark. lwm@novonordisk.com
authors.forename: Lars Wichmann
authors.initials: LW
authors.lastname: Madsen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: Carsten
authors.initials: C
authors.lastname: Gotfredsen
authors.forename: Andrew
authors.initials: A
authors.lastname: Pilling
authors.forename: Ingrid
authors.initials: I
authors.lastname: Sjögren
authors.forename: Søren
authors.initials: S
authors.lastname: Andersen
authors.forename: Lene
authors.initials: L
authors.lastname: Andersen
authors.forename: Anne Sietske
authors.initials: AS
authors.lastname: de Boer
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Afsar
authors.initials: A
authors.lastname: Barlas
authors.forename: Sushil
authors.initials: S
authors.lastname: Vundavalli
authors.forename: Niels C Berg
authors.initials: NC
authors.lastname: Nyborg
authors.forename: Lotte Bjerre
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Moelck
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000097:blood / Q000378:metabolism; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D000069450:Liraglutide; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D010750:Phosphoproteins / Q000737:chemistry; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D018027:Receptors, Glucagon / Q000819:agonists*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013997:Time Factors
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010750:Phosphoproteins; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; D058570:TOR Serine-Threonine Kinases