Endocrine pharmacologyEffect of exendin (exenatide)—GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model☆
Introduction
Exenatide or exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes (Denker and Dimarco, 2006, Goke et al., 1993, Ahmad and Swann, 2008). The native compound is rapidly degraded by dipeptidyl peptidase-4, this in turn triggered development of more clinically useful forms with prolonged half-lives, including exenatide. GLP-1 is a gastrointestinal hormone which regulates blood glucose primarily via the stimulation of the glucose dependent insulin release (De Leon et al., 2006).
The actions of GLP-1 are mediated by a G protein coupled receptor, and the sequence is highly conserved in mammals (Mayo et al., 2003, Bjerre Knudsen et al., 2010) with a 93% homology between rat and human. Studies with rat thyroid C-cell lines and thyroid tissues have shown that activation of the GLP-1 receptor leads to calcitonin secretion (Lamari et al., 1996) and one clinical GLP-1 agonist, liraglutide, has been shown to cause C cell hyperplasia in rodents. Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice (Drug Facts and online, 2008). It is postulated that liraglutide by persistent calcitonin secretion and synthesis could drive up C cell hyperplasia (Parola, 2009), and further that C cell proliferation occurs along a continuum ranging from diffuse hyperplasia to adenomas and carcinomas.
There are limited studies evaluating the effect of exenatide on the thyroid. There also appear to be no reports about the effect of exenatide on the parathyroid gland or on calcium homeostasis, another potential effect of increased calcitonin expression. The aim of this study was to evaluate the effect of exendin-4 on thyroid and parathyroid cells in a rat model.
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Animals
Thyroid studies utilized 20 ∼8-week-old outbred Sprague-Dawley male rats, 10 controls, and 10 drug-treated rats. Animals were housed in an AAALAC-approved facility and maintained at constant temperature of 72 °F and humidity (30%) on a 12 h light–dark cycle throughout the experimental period, with free access to chow and water. Chow was Harlan Teklad TD94149 Control chow with defined, complete minerals and vitamins, 15.4% protein, 63.1% carbohydrate and 10% fat. Experiments were performed with
Calcitonin
The thyroid tissue of rats treated with exendin receiving the control diet had several cells that stained positive for calcitonin. The intensity of staining differed from mild to very intense (Fig. 1A). The stain was greatest in the cell cytoplasm. Glands of the controls demonstrated a very weak staining for calcitonin in interstitial cells (Fig. 1B). Fig. 2 summarizes the average number and the cellular intensity of calcitonin positive cells in the thyroid glands of the rats of both groups.
Discussion
In this study there was significant C cell hypertrophy and calcitonin staining seen in the thyroid of rats treated with exendin-4. Glucagon like peptide-1 (GLP-1) is released into the circulation by the gastrointestinal L cells which occurs in response to nutrient ingestion and this in turn activates the GLP-1 receptor (Ban et al., 2010). The activation of GLP 1 receptor stimulates the production of insulin by beta cells and decreases glucagon production thus helping the hyperglycemia in
Conclusions
In summary, the use of exendin-4 in rodents caused increase in the calcitonin cellular expression and C cell hyperplasia, morphological changes in the interstitial glandular section, and the presence of a few CEA positive stained cells. No damage was apparent in the parathyroids nor was serum calcium levels changed. These data, however, raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.
Conflicts of interest
None to report.
Acknowledgments
The authors thank Dr. Gurmukh Singh, Director of Laboratory Medicine Section, Department of Pathology, UMKC School of Medicine and the histology technologists Audrey Lammer Supervisor with technicians Maxine Amos, Stacey Mott and Connie Parker for their helpful input to this study.
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Funding: This study was funded by the Saint Luke's Foundation Grant, Kansas City.