title: Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.
abstract: Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.
authors.affiliation: Department of Biology and Pharmacology Mgt, Novo Nordisk A/S, Novo Nordisk Park, Maaloev DK-2760, Denmark. lbkn@novonordisk.com
authors.forename: Lotte
authors.initials: L
authors.lastname: Bjerre Knudsen
authors.forename: Lars Wichmann
authors.initials: LW
authors.lastname: Madsen
authors.forename: Søren
authors.initials: S
authors.lastname: Andersen
authors.forename: Kasper
authors.initials: K
authors.lastname: Almholt
authors.forename: Anne S
authors.initials: AS
authors.lastname: de Boer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Carsten
authors.initials: C
authors.lastname: Gotfredsen
authors.forename: Frederikke Lihme
authors.initials: FL
authors.lastname: Egerod
authors.forename: Anne Charlotte
authors.initials: AC
authors.lastname: Hegelund
authors.forename: Helene
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Søren Dyring
authors.initials: SD
authors.lastname: Jacobsen
authors.forename: Alan C
authors.initials: AC
authors.lastname: Moses
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mølck
authors.forename: Henriette S
authors.initials: HS
authors.lastname: Nielsen
authors.forename: Jette
authors.initials: J
authors.lastname: Nowak
authors.forename: Helene
authors.initials: H
authors.lastname: Solberg
authors.forename: Tu D L
authors.initials: TD
authors.lastname: Thi
authors.forename: Milan
authors.initials: M
authors.lastname: Zdravkovic
authors.forename: Ulrik
authors.initials: U
authors.lastname: Moerch
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002116:Calcitonin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D000069450:Liraglutide; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D002116:Calcitonin; D000242:Cyclic AMP