Glucagon-Like Peptide-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell Proliferation

• DOI: 10.1210/en.2009-1272
• Publication Date: 2010-03-05T03:05:16Z
• Authors: Lotte Bjerre Knudsen; Lars Wichmann Madsen; Søren Andersen; Kasper Almholt; Anne S. de Boer; Daniel J. Drucker; Carsten Gotfredsen; Frederikke Lihme ...; Anne Charlotte He...; Helene Jacobsen; Søren Dyring Jaco...; Alan C. Moses; Anne-Marie Mølck; Henriette S. Nielsen; Jette Nowak; Helene Solberg; Tu D. L. Thi; Milan Zdravkovic
• Keywords: Calcitonin receptor; Glucagon receptor

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 GLP-1 receptor-mediated mechanism these changes rodents. The receptor localized to rodent C-cells. agonists stimulated calcitonin release, up-regulation of gene expression, subsequently rats and, lesser extent, mice. In contrast, humans and/or cynomolgus monkeys had low expression C-cells, did not activate adenylate cyclase or generate release primates. Moreover, 20 months treatment (at >60 times human levels) lead monkeys. Mean levels patients exposed yr remained at the lower end normal range, there no difference proportion increasing above clinically relevant cutoff level pg/ml. Our findings delineate important species-specific differences action thyroid. Nevertheless, long-term consequences sustained activation remain unknown merit further investigation.