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.

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

“…Another reason could be that GLP-1 agonists do not act directly on bone cells. It has been shown that GLP1-R is also expressed in C cells of the thyroid gland and exerts, when activated by GLP-1 or its stable analogues, a stimulating effect on calcitonin secretion in rodents (63,64), a potent inhibitor of bone resorption. As proposed by Yamada et al (29), GLP-1 agonist effects on bone might be indirect rather than direct, acting mainly by targeting calcitonin secretion from the thyroid to modulate bone turnover.…”

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

“…While several studies have reported that the GLP-1 mimetics do not induce pancreatitis in rats, mouse and/or monkey 47– 49 , these studies did not include DPP4 inhibitors, which are the compounds that might be responsible for interactions with pancreatic proteins according to our study. It is to be noted however that these mimetics may have other physiological effects and ‘the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation’ 50 . Once again, the previous study 50 has been challenged by another group who note that ‘findings previously reported in rodents may not apply to humans’ 51 .…”

“…It is to be noted however that these mimetics may have other physiological effects and ‘the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation’ 50 . Once again, the previous study 50 has been challenged by another group who note that ‘findings previously reported in rodents may not apply to humans’ 51 .…”

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

“…24,33 In contrast to rodents, GLP-1 receptor expression on primate thyroid C-cells is very low, and no changes have been observed with in vitro stimulation of human C-cells by GLP-1 receptor agonists. 10,24 Patients with a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2 (MEN2) will be excluded from ESXCEL. Patients randomized into EXSCEL will have their study medication discontinued if their screening calcitonin value is >40 ng/L, or subsequent annual values are ≥50 ng/L.…”

“…In view of concerns raised in animal studies about a possible increase in thyroid C-cell adenomas and carcinomas, 24,25 the FDA has requested that calcitonin be assayed by a central laboratory at screening and annually thereafter. These will be scrutinised centrally.…”