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 Journal Article

   

Authors:	Madsen, L. W.; Knauf, J. A.; Gotfredsen, C.; Pilling, A.; Sjögren, I.; Andersen, S.; Andersen, L.; De Boer, A. S.; Manova, K.; Barlas, A.; Vundavalli, S.; Berg Nyborg, N. C.; Knudsen, L. B.; Moelck, A. M.; Fagin, J. A.
Article 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. Copyright © 2012 by The Endocrine Society.
Keywords:	immunohistochemistry; signal transduction; mitogen activated protein kinase; s6 kinase; controlled study; histopathology; nonhuman; animal cell; mouse; animal tissue; animal experiment; animal model; calcitonin; wild type; gene activation; enzyme phosphorylation; cell hyperplasia; oncogene ret; calcitonin blood level; thyroid parafollicular cell; exendin 4; glucagon like peptide 1 receptor; liraglutide
Journal Title:	Endocrinology
Volume:	153
Issue:	3
ISSN:	0013-7227
Publisher:	Endocrine Society
Date Published:	2012-03-01
Start Page:	1538
End Page:	1547
Language:	English
DOI:	10.1210/en.2011-1864
PROVIDER:	scopus
PMCID:	PMC3281535
PUBMED:	22234463
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84857422717&partnerID=40&md5=ee6b48e4d85f475e4c87e52ff85ac4b2
Notes:	--- - "Export Date: 2 April 2012" - "CODEN: ENDOA" - "Source: Scopus"

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