Article

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

1The Ohio State University, Department of Veterinary Biosciences, Columbus, Ohio, USA.
Toxicologic Pathology (Impact Factor: 1.92). 03/2013; 41(2):303-9. DOI: 10.1177/0192623312472402
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
55 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
    12/2014; 5(6):817-34. DOI:10.4239/wjd.v5.i6.817
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A review of the literature of chemically induced lesions of the endocrine organs indicates that the adrenal glands are the most commonly affected, followed in descending order by the thyroid, pancreas, pituitary, and parathyroid glands. In the adrenal glands, chemically induced lesions are found most frequently in the zona fasciculata, zona reticularis and, to a lesser extent, in either the zona glomerulosa or the medulla. In a survey of tumor types developing in carcinogenicity studies, conducted by the Pharmaceutical Manufacturers Association, endocrine tumors developed frequently in rats. The thyroid gland was third in frequency (behind liver and mammary gland), followed by the pituitary gland (fourth) and adrenal gland (fifth). For purposes of the following discussion, pharmacological as well as toxicologic effects will be reviewed, with emphasis on the latter. Pharmacological effects are defined as beneficial and desired drug-related changes with minimal side effects and morphological alterations (which are often reversible), whereas toxicologic effects are more severe adverse effects that often are irreversible.
    Haschek and Rousseaux's Handbook of Toxicologic Pathology, Third edited by Wanda Haschek, Colin Rousseaux, Matthew Wallig, 01/2013: chapter Endocrine System: pages 2391-2491; Academic Press.

Full-text

Download
22 Downloads
Available from
May 22, 2014