title: Hepatic portal vein denervation impairs oral glucose tolerance but not exenatide's effect on glycemia.
abstract: The hepatoportal area is an important glucohomeostatic metabolic sensor, sensing hypoglycemia, hyperglycemia, and hormones such as glucagon-like peptide-1 (GLP-1). We have reported previously that activation of hepatoportal sensors by intraportal infusion of glucose and GLP-1 or by subcutaneous administration of GLP-1 receptor activator exenatide and of intraportal glucose improved glycemia independent of corresponding changes in pancreatic hormones. It is not clear whether this effect is mediated via the portal vein (PV) or by direct action on the liver itself. To test whether receptors in the PV mediate exenatide's beneficial effect on glucose tolerance, we performed 1) paired oral glucose tolerance tests (OGTT) with and without exenatide and 2) intravenous glucose tolerance tests before and after PV denervation in canines. Denervation of the portal vein affected oral glucose tolerance; post-denervation (POST-DEN) OGTT glucose and insulin AUC were 50% higher than before denervation (P = 0.01). However, portal denervation did not impair exenatide's effect to improve oral glucose tolerance (exenatide effect: 48 ± 12 mmol·l⁻¹·min before vs. 64 ± 26 mmol·l⁻¹·min after, P = 0.67). There were no changes in insulin sensitivity or secretion during IVGTTs. Portal vein sensing might play a role in controlling oral glucose tolerance during physiological conditions but not in pharmacological activation of GLP-1 receptors by exenatide.
authors.affiliation: Diabetes and Obesity Research Institute and Viorica.Ionut@cshs.org.
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Ana Valeria B
authors.initials: AV
authors.lastname: Castro
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Orison O
authors.initials: OO
authors.lastname: Woolcott
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Malini S
authors.initials: MS
authors.lastname: Iyer
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Josiane L
authors.initials: JL
authors.lastname: Broussard
authors.affiliation: Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Miguel
authors.initials: M
authors.lastname: Burch
authors.affiliation: Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Ram
authors.initials: R
authors.lastname: Elazary
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Kolka
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Hasmik
authors.initials: H
authors.lastname: Mkrtchyan
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Isaac Asare
authors.initials: IA
authors.lastname: Bediako
authors.affiliation: Diabetes and Obesity Research Institute and.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D003433:Crosses, Genetic; D003714:Denervation; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000209:etiology / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000209:etiology / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011169:Portal Vein / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology* / Q000601:surgery; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D014446:Tyrosine 3-Monooxygenase
keywords: denervation; exenatide; glucagon-like peptide-1; hepatic portal vein