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.

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

“…Our data indicate that Ex-4 stimulates calcitonin secretion and thus can induce an inhibition of resorption. However we found no effect of LIR on calcitonin secretion while studies have reported that both Ex-4 and LIR stimulate calcitonin secretion (63,64). Our data are not completely consistent with this mechanism since we observed an increase in resorption surfaces with GLP-1 agonists whereas other studies have reported that calcitonin decreased resorption surfaces (65).…”

“…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.…”

Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor

“…Calcitonin is one of the most efficient inhibitors of bone resorption in vitro (Zaidi et al 1990, Moonga et al 1992. Evidence from previous studies suggests that basally, male Glp1r KO mice present with a 2.5-fold increase in circulating plasma calcitonin (Madsen et al 2012). As regard to the inhibitory action of calcitonin on bone resorption, it would be legitimate to hypothesize that bone resorption should be the primary target of calcitonin increase.…”

Adverse Effects of GLP-1 Receptor Agonists

“…Liraglutide and exenatide have been associated with the development of thyroid C-cell tumors in rodents after life-time exposure at supratherapeutic doses [169]. Furthermore, a 13-week continuous exposure to GLP-1 receptor agonists induced marked increases in plasma calcitonin and in the incidence of C-cell hyperplasia in wild-type mice, but not in GLP-1 receptor knockout mice [170]. In contrast to the results in rodents, in vivo animal studies with cynomologus monkeys did not show any liraglutideinduced calcitonin release or any effect on relative C-cell fraction in the thyroid gland after 87 weeks at doses up to 60-fold higher than the highest dose recommended in humans [169].…”