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

Endocrinology. 2012 Mar;153(3):1538-47. doi: 10.1210/en.2011-1864. Epub 2012 Jan 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcitonin / blood
  • Calcitonin / metabolism
  • Female
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Immunohistochemistry / methods
  • Ligands
  • Liraglutide
  • Male
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Phosphoproteins / chemistry
  • Proto-Oncogene Proteins c-ret / genetics
  • Receptors, Glucagon / agonists*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Thyroid Gland / metabolism*
  • Time Factors


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Phosphoproteins
  • Receptors, Glucagon
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Calcitonin
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-ret