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 Ͼ60 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.

Eksenatid Tedavisinde Tiroid İnce İğne Aspirasyon Biyopsisi ve Kalsitonin Yıkamanın Yeri Role of Thyroid Fine Needle Aspiration Biopsy and Calcitonin Wash-Out During Exenatide Therapy

“…In vitro sıçan ve farelerde eksenatid ile C hücrelerinde bulunan GLP-1 reseptörlerinin uyarılması sonucu Ct salınımı ve Ct gen ekspresyonu artar ve CHH gelişir (8,9). GLP-1 knock-out farelerde eksenatid ile Ct artışı gözlenmemiştir (2,8).…”

“…GLP-1 knock-out farelerde eksenatid ile Ct artışı gözlenmemiştir (2,8). In vitro insan TT C hücrelerinde ise GLP-1 reseptörleri azdır ve GLP-1'e fonksiyonel yanıt görülmemiştir (2,5,10).…”

“…In vitro insan TT C hücrelerinde ise GLP-1 reseptörleri azdır ve GLP-1'e fonksiyonel yanıt görülmemiştir (2,5,10). İnsan C hücre neoplazmalarının sadece %27'sinde GLP-1 reseptörü bulunmuştur (8). Normal tiroid glandında C hücre yoğunluğu açısından primatlar insan modeline daha yakındır (2,9 …”

Update on Safety Issues Related to Antihyperglycemic Therapy

“…In rats and rodents, liraglutide was shown to stimulate calcitonin secretion and increase the incidence of C-cell hyperplasia and therefore medullary thyroid carcinoma. 58 It is important to note that human C cells have significantly fewer GLP-1 receptors than those of rodents, and studies have not shown the same changes in monkeys, which are more closely related to humans. 58 Despite the absence of a definite relationship between MTC and liraglutide in humans, it is recommended that the agent not be given to patients with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2.…”

Role of conventional oral antidiabetic drugs in management of type 2 diabetes mellitus

“…low grade inflammation and high levels of GLP-1 activity will predispose to the development of pancreatic cancer.  Thyroid cancer-In carcinogenicity studies with liraglutide, C cell tumours were observed in thyroid tissue of mice and rats, and C-cells were observed to proliferate in response to GLP-1 agonist therapy [28,29] …”