title: Effects of prolonged exendin-4 administration on hypothalamic-pituitary-adrenal axis activity and water balance.
abstract: Exendin-4 (Ex-4) is a natural agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently being used as a treatment for type 2 diabetes mellitus due to its insulinotropic properties. Previous studies have revealed that acute administration of both GLP-1 and, in particular, Ex-4 potently stimulates hypothalamic-pituitary-adrenal (HPA) axis activity. In this work, the effects of prolonged Ex-4 exposure on HPA function were explored. To this end, Sprague-Dawley rats were subjected to a daily regimen of two Ex-4 injections (5 μg/kg sc) for a minimum of 7 days. We found that subchronic Ex-4 administration produced a number of effects that resemble chronic stress situations, including hyperactivation of the HPA axis during the trough hours, disruption of glucocorticoid circadian secretion, hypertrophy of the adrenal gland, decreased adrenal gland sensitivity, impaired pituitary-adrenal stress responses, and reductions in both food intake and body weight. In addition, a threefold increase in diuresis was observed followed by a 1.5-fold increase in water intake; these latter effects were abolished by adrenalectomy. Together, these findings indicate that Ex-4 induces a profound dysregulation of HPA axis activity that may also affect renal function.
authors.affiliation: Laboratory of Endocrinology, Center for Biomedical Research, Campus As Lagoas-Marcosende, University of Vigo, Vigo, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gil-Lozano
authors.forename: Marina
authors.initials: M
authors.lastname: Romaní-Pérez
authors.forename: Verónica
authors.initials: V
authors.lastname: Outeiriño-Iglesias
authors.forename: Eva
authors.initials: E
authors.lastname: Vigo
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
authors.forename: Lucas C
authors.initials: LC
authors.lastname: González-Matías
authors.forename: Federico
authors.initials: F
authors.lastname: Mallo
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D004435:Eating / Q000502:physiology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000502:physiology; D014688:Venoms / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000187:drug effects*
chemical_list: D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000324:Adrenocorticotropic Hormone; D000077270:Exenatide; D003345:Corticosterone
keywords: adrenal; circadian; corticosterone; diuresis; exendin-4