title: Exendin-4 increases blood glucose levels acutely in rats by activation of the sympathetic nervous system.
abstract: Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), shares many of the actions of GLP-1 on pancreatic islets, the central nervous system (CNS), and the gastrointestinal tract that mediates glucose homeostasis and food intake. Because Ex-4 has a much longer plasma half-life than GLP-1, it is an effective drug for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Here, we report that acute administration of Ex-4, in relatively high doses, into either the peripheral circulation or the CNS, paradoxically increased blood glucose levels in rats. This effect was independent of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of Ex-4 and could be blocked by a GLP-1R antagonist. Comparable doses of GLP-1 did not induce hyperglycemia, even when protected from rapid metabolism by a dipeptidyl peptidase IV inhibitor. Acute hyperglycemia induced by Ex-4 was blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that this effect was mediated by sympathetic nervous system (SNS) activation. The potency of Ex-4 to elevate blood glucose waned with chronic administration such that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were evident. These findings indicate that, in rats, high doses of Ex-4 activate a SNS response that can overcome the expected benefits of this peptide on glucose metabolism and actually raise blood glucose. These results have important implications for the design and interpretation of studies using Ex-4 in rats. Moreover, since there are many similarities in the response of the GLP-1R system across mammalian species, it is important to consider whether there is acute activation of the SNS by Ex-4 in humans.
authors.affiliation: Department of Functional Biology and Health Sciences, Faculty of Biology, Laboratory of Endocrinology, Campus of Vigo, As Lagoas-Marcosende, University of Vigo, E-36310 Vigo, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Pérez-Tilve
authors.forename: Lucas
authors.initials: L
authors.lastname: González-Matías
authors.forename: Benedikt A
authors.initials: BA
authors.lastname: Aulinger
authors.forename: Mayte
authors.initials: M
authors.lastname: Alvarez-Crespo
authors.forename: Manuel
authors.initials: M
authors.lastname: Gil-Lozano
authors.forename: Elias
authors.initials: E
authors.lastname: Alvarez
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Andrade-Olivie
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: David A
authors.initials: DA
authors.lastname: D'Alessio
authors.forename: Federico
authors.initials: F
authors.lastname: Mallo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008297:Male; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide