Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.
Level 5 - mechanism / opinion, no new human data
Comparative mechanistic bench and animal research combined with human clinical trial safety follow-up data.
PubMed 20203154 · doi:10.1210/en.2009-1272
What was done
Researchers investigated the mechanism of liraglutide-induced thyroid C-cell hyperplasia and tumors across species. They evaluated glucagon-like peptide-1 (GLP-1) receptor localization and activation (adenylate cyclase activation, calcitonin gene expression, and calcitonin release) in rodent, cynomolgus monkey, and human thyroid tissues. They also examined thyroid histology in cynomolgus monkeys treated with liraglutide for 20 months at >60 times human exposure levels, and monitored circulating calcitonin levels in human patients treated with liraglutide for 2 years.
What was found
GLP-1 receptors localized to rodent C-cells, where agonists stimulated calcitonin release, up-regulated calcitonin gene expression, and produced C-cell hyperplasia in rats and to a lesser extent in mice. In contrast, human and cynomolgus monkey thyroid C-cells had low GLP-1 receptor expression, and GLP-1 receptor agonists did not activate adenylate cyclase or stimulate calcitonin release in primates. Monkeys treated for 20 months at >60 times human exposure did not develop C-cell hyperplasia. In humans treated with liraglutide for 2 years, mean calcitonin levels remained at the lower end of the normal range, and the proportion of patients with calcitonin exceeding the 20 pg/ml cutoff did not differ. Specific group numbers, exact mean values, and p-values were not reported in the abstract.
Why it matters
This study demonstrates marked species differences in thyroid GLP-1 receptor expression and signaling, explaining why rodent thyroid C-cell proliferation and neoplasia may not directly translate to primates or humans.
Limits
The abstract omits exact sample sizes for animal and human groups, as well as quantitative baseline and endpoint values. The long-term consequences of sustained GLP-1 receptor activation in the human thyroid beyond 2 years remain unknown.
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