Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man

Abstract

Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression of GLP1R is much lower in primates than in rodents, the described C-cell proliferative lesions may not be relevant to man. Here, we aimed to establish primary thyroid cell cultures of rat and human to evaluate the expression and function of GLP1R in C-cells. In our experiments, GLP1R expression was observed in primary rat C-cells (in situ hybridization) but was not detected in primary human C-cells (mRNA and protein levels). The functional response of the cultures to the stimulation with GLP1R agonists is an indirect measure of the presence of functional receptor. Liraglutide and taspoglutide elicited a modest increase in calcitonin release and in calcitonin expression in rat primary thyroid cultures. Contrarily, no functional response to GLP1R agonists was observed in human thyroid cultures, despite the presence of few calcitonin-positive C-cells. Thus, the lack of functional response of the human cultures adds to the weight of evidence indicating that healthy human C-cells have very low levels or completely lack GLP1R. In summary, our results support the hypothesis that the GLP1R agonist-induced C-cell responses in rodents may not be relevant to primates. In addition, the established cell culture method represents a useful tool to study the physiological and/or pathological roles of GLP1 and GLP1R agonists on normal, non-transformed primary C-cells from rats and man.

Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas

“…21 In humans, however, using the same method, approximately 1/3 of the cases of medullary thyroid carcinomas, but none of the normal thyroids, had GLP1R. 2,21 These species differences were confirmed by Bjerre-Knudsen et al 15 and Boess et al 16 A subsequent immunohistochemical study by Gier et al 22 in human thyroid tissues, however, has suggested that normal human thyroid and various thyroid pathologies can often express GLP1R. The authors concluded that caution was necessary when treating patients with incretins.…”

“…[11][12][13] On one hand, it was observed in preclinical animal studies that a significant number of animals developed medullary thyroid carcinomas after long-term treatment with GLP1 analogs. [14][15][16] On the other hand, there have been reports suggesting that GLP1 analogs may induce pancreatitis or pancreatic cancers. 12,17,18 These studies are presently taken very seriously and weighted with regard to the benefits of incretin therapy in diabetes.…”

Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes: A Clinical Update of Safety and Efficacy

“…Long-term exposure to liraglutide in rodents, but not monkeys, has been associated with thyroid C-cell hyperplasia and tumors through a GLP-1 receptor-mediated mechanism [75]. As an explanation for differences between rodents and nonhuman primates, it has been shown that humans and nonhuman primates have very low thyroid C-cell density and GLP-1 receptor expression compared with rodents; therefore, GLP-1 RA-induced C-cell responses in rodents may not be relevant to primates [75, 76]. As is also true for examining risk of pancreatitis and pancreatic cancer, longer-term studies are needed to further evaluate sustained GLP-1 receptor activation in the human thyroid system.…”

The bone-preserving effects of exendin-4 in ovariectomized rats

“…Second, we did not measure serum markers of bone formation and resorption, nor did we measure calcitonin levels. GLP-1 RAs, including exendin-4, can stimulate calcitonin release from the C cells of the thyroid in rodents but not in humans [22,29,30], leading to inhibition of bone resorption [22]. Thus, the bone-preserving effects of exendin-4 in OVX rats might be multi-factorial.…”