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: 2.14). 03/2013; 41(2):303-9. DOI: 10.1177/0192623312472402
Source: PubMed


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.

Download full-text


Available from: Thomas Rosol, Mar 26, 2014
  • 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.
    Full-text · Chapter · Dec 2013
  • Source
    [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.
    Preview · Article · Dec 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: GLP-1 and its analogs have a variety of anti-diabetic effects. However, short half-life and rapid degraded by DPP-IV limits the therapeutic potential of the native GLP-1. So, many DPP-IV-resistant and long-acting GLP-1 analogs were developed. In this study, an antibody-like extendin-4-IgG4 fusion protein was developed. The γ4 constant region contains two amino acid substitutions relative to native γ4 (S228P and L235E) lead to affinity for FcγRI to be low and stability of the IgG4 molecular. The fusion protein was expressed in CHO cells and assembled into an immunoglobulin-like structure with molecular weight of approximately 130 kDa. The Exendin-4-IgG4 fusion protein was found to affinity bind GLP-1R in vitro. In vivo when compared the potency and duration of glucose-lowering effects in diabetic (db/db) mice at the same dose, exendin-4 resulted in a glucose-lowering effect that persisted only for 6 hours, but the extendin-4-IgG4 fusion protein for more than 168 hours. Injecting subcutaneously with a high dose of the fusion protein led normal BALB/c mice to the lower blood glucose level but did not cause serious hypoglycemia. Especially, the half-life time of the fusion protein in cynomolgus monkeys was about 180 hours, almost the longest half-life time among the developed GPL-1 analogues, which suggested a longer half-life time in human. The intact antibody-like fusion protein has more advantages than the Fc fusion protein including the intent of prolonging the half-life. These results also suggested the fusion protein was a safe and long-acting potential anti-diabetic agent.
    No preview · Article · Jun 2015 · International Journal of Clinical and Experimental Medicine
Show more