On-target Effects of GLP-1 Receptor Agonists on Thyroid C-cells in Rats and Mice

Glucagon-like peptide-1 is an incretin hormone from the gastrointestinal tract, which enhances insulin secretion, slows gastric emptying, and reduces food intake. GLP-1 receptor agonists are being developed for Type 2 diabetes mellitus. GLP-1 is rapidly degraded by serum dipeptidyl peptidase IV, so analogues with a prolonged serum half-life are used clinically. Exenatide was the first GLP-1 agonist approved and is a synthetic version of exendin-4 derived from the Gila monster. Liraglutide was approved for clinical use in 2010. GLP-1 receptor agonists have been shown to increase calcitonin secretion and stimulate C-cell hyperplasia and neoplasia in rats and mice of both sexes. Rat C-cells are more sensitive to the effects of GLP-1 agonists than mice. The effects of GLP-1 agonists on C-cell proliferation or neoplasia have not been documented in nonhuman primates or humans. The proliferative C-cell effects may be rodent-specific. GLP-1 receptors have been demonstrated on normal rodent C-cells, but are either not present or occur in low numbers on C-cells of nonhuman primates and humans. Hyperplasia and neoplasia of C-cells in rodents treated with GLP-1 agonists represent a unique example of an on-target species-specific effect that may not have relevance to humans.