Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation

Endocrinology. 2010 Apr;151(4):1473-86. doi: 10.1210/en.2009-1272. Epub 2010 Mar 4.


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.

Publication types

  • Clinical Trial

MeSH terms

  • Animals
  • Blotting, Western
  • Calcitonin / genetics
  • Calcitonin / metabolism*
  • Cell Line
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression / drug effects
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Liraglutide
  • Macaca fascicularis
  • Mice
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Radioimmunoassay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Species Specificity
  • Thyroid Gland / cytology
  • Thyroid Gland / drug effects*
  • Thyroid Gland / metabolism


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • RNA, Messenger
  • Receptors, Glucagon
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Calcitonin
  • Cyclic AMP