title: The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1.
abstract: The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions on separate occasions. At t = 15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg(-1)·min(-1)) from t = 45-95 min and at a higher dose (1 pmol·kg(-1)·min(-1)) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P < 0.002] and suppression of pancreatic polypeptide levels [area under the curve during the GLP-1 infusions (AUC45-145): 492 ± 85 (saline) vs. 247 ± 59 (atropine) pmol/l × min, P < 0.0001]. More glucose was needed to maintain the clamp during the high-dose GLP-1 infusion steady-state period on the atropine day [6.4 ± 0.9 (saline) vs. 8.7 ± 0.8 (atropine) mg·kg(-1)·min(-1), P < 0.0023]. GLP-1 dose-dependently increased insulin secretion on both days. The insulinotropic effect of GLP-1 was not impaired by atropine [C-peptide AUCs45-145: 99 ± 8 (saline) vs. 113 ± 13 (atropine) nmol/l × min, P = 0.19]. Atropine suppressed glucagon levels additively with GLP-1 [AUC45-145: 469 ± 70 (saline) vs. 265 ± 50 (atropine) pmol/l × min, P = 0.018], resulting in hypoglycemia when infusions were suspended [3.6 ± 0.2 (saline) vs. 2.7 ± 0.2 (atropine) mmol/l, P < 0.0001]. To ascertain whether atropine could independently suppress glucagon levels, control experiments (n = 5) were carried out without GLP-1 infusions [AUC45-145: 558 ± 103 (saline) vs. 382 ± 76 (atropine) pmol/l × min, P = 0.06]. Our results suggest that efferent muscarinic activity is not required for the insulinotropic effect of exogenous GLP-1 but that blocking efferent muscarinic activity independently suppresses glucagon secretion. In combination, GLP-1 and muscarinic blockade strongly affect glucose turnover.
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Astrid
authors.initials: A
authors.lastname: Plamboeck
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and Department of Surgical Gastroenterology and Liver Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Veedfald
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark;
authors.forename: Tina
authors.initials: T
authors.lastname: Vilsbøll
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Knop
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; and jjholst@sund.ku.dk.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000328:Adult; D001285:Atropine / Q000008:administration & dosage; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003718:Denmark; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism; D005934:Glucagon / Q000097:blood*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D015309:Glucose Clamp Technique; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood*; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D016037:Single-Blind Method; D013004:Somatostatin / Q000097:blood; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D018727:Muscarinic Antagonists; D013004:Somatostatin; D001285:Atropine; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000109:Acetylcholine
keywords: GLP-1; atropine; glucagon; insulin; vagal efferent signaling; vagus nerve