title: Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog.
abstract: Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg⁻¹·min⁻¹, Ex-4-low; n = 5) or high (0.9 pmol·kg⁻¹·min⁻¹, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg⁻¹·min⁻¹ between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg⁻¹·min⁻¹), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. dale.edgerton@vanderbilt.edu
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.forename: Zhibo
authors.initials: Z
authors.lastname: An
authors.forename: Kathryn M S
authors.initials: KM
authors.lastname: Johnson
authors.forename: Tiffany
authors.initials: T
authors.lastname: Farmer
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Doss
authors.initials: D
authors.lastname: Neal
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D003243:Consciousness; D004285:Dogs; D000077270:Exenatide; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000097:blood / Q000494:pharmacology*; D011169:Portal Vein; D014688:Venoms / Q000097:blood / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D019344:Lactic Acid; D000077270:Exenatide; D005947:Glucose
keywords: exenatide; exendin-4; hepatic glucose metabolism; hepatic glucose production; hepatic glucose uptake; incretin