title: Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways.
abstract: We previously reported that glucagon-like peptide-1 (GLP-1) appearance in the portal vein facilitates hepatic vagal afferent activity, and this further augments reflexively the pancreatic vagal efferents in anesthetized rats, suggesting a neuroincretin effect of GLP-1. To determine whether the GLP-1-induced vagal pathways lead to a neuronal-mediated component (NMC) of insulin secretion, we infused GLP-1 at a physiological or pharmacological dose (1 or 3 pmol·kg(-1)·min(-1), respectively) into the portal vein in conscious rats with selective hepatic vagotomy (Vagox) or sham operation (Sham). The experiments consisted of two sequential 10-min intraportal infusions (P1 and P2): glucose at a physiological rate (56 μmol·kg(-1)·min(-1)) in P1 and the glucose plus GLP-1 or vehicle in P2. Under arterial isoglycemia across the groups, the physiological GLP-1 infusion in Sham augmented promptly and markedly arterial insulin levels, approximately twofold the levels in glucose alone infusion (P < 0.005), and insulin levels in Vagox diminished apparently (P < 0.05). Almost 60% of the GLP-1-induced insulin secretion (AUC) in Sham met the NMC, i.e., difference between insulin secretion in Sham and Vagox, (AUC 976 ± 65 vs. 393 ± 94 pmol·min/l, respectively, P < 0.005). Intraportal pharmacological GLP-1 infusion further augmented insulin secretion in both groups, but the NMC remained in 46% (NS; Sham vs. Vagox). In contrast, "isoglycemic" intravenous GLP-1 infusion (3 pmol·kg(-1)·min(-1)) evoked an equal insulin secretion in both groups. Thus, the present results indicate that GLP-1 appearing in the portal vein evokes a powerful neuronal-mediated insulinotropic effect, suggesting the neuroincretin effect.
authors.affiliation: Division of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa Japan. makoto@kanazawa-med.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakabayashi
authors.forename: Keigo
authors.initials: K
authors.lastname: Uehara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Kenzo
authors.initials: K
authors.lastname: Uchida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D055724:Electrophysiological Phenomena / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D054795:Incretins / Q000502:physiology; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011169:Portal Vein / Q000502:physiology*; D019518:Postprandial Period / Q000502:physiology; D051381:Rats; D012018:Reflex / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D054795:Incretins; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: glucose-induced early-phase insulin secretion; hepatic vagotomy; unrestrained conscious rat; vagal hormone reception