title: Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog.
abstract: The impact of the GLP-1 receptor agonist lixisenatide on postprandial glucose disposition was examined in conscious dogs to identify mechanisms for its improvement of meal tolerance in humans and examine the tissue disposition of meal-derived carbohydrate. Catheterization for measurement of hepatic balance occurred ≈16 days before study. After being fasted overnight, dogs received a subcutaneous injection of 1.5 μg/kg lixisenatide or vehicle (saline, control; n = 6/group). Thirty minutes later, they received an oral meal feeding (93.4 kJ; 19% protein, 71% glucose polymers, and 10% lipid). Acetaminophen was included in the meal in four control and five lixisenatide dogs for assessment of gastric emptying. Observations continued for 510 min; absorption was incomplete in lixisenatide at that point. The plasma acetaminophen area under the curve (AUC) in lixisenatide was 65% of that in control (P < 0.05). Absorption of the meal began within 15 min in control but was delayed until ≈30-45 min in lixisenatide. Lixisenatide reduced (P < 0.05) the postprandial arterial glucose AUC ≈54% and insulin AUC ≈44%. Net hepatic glucose uptake did not differ significantly between groups. Nonhepatic glucose uptake tended to be reduced by lixisenatide (6,151 ± 4,321 and 10,541 ± 1,854 μmol·kg(-1)·510 min(-1) in lixisenatide and control, respectively; P = 0.09), but adjusted (for glucose and insulin concentrations) values did not differ (18.9 ± 3.8 and 19.6 ± 7.9 l·kg(-1)·pmol(-1)·l(-1), lixisenatide and control, respectively; P = 0.94). Thus, lixisenatide delays gastric emptying, allowing more efficient disposal of the carbohydrate in the feeding without increasing liver glucose disposal. Lixisenatide could prove to be a valuable adjunct in treatment of postprandial hyperglycemia in impaired glucose tolerance or type 2 diabetes.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, and.
authors.forename: Mary Courtney
authors.initials: MC
authors.lastname: Moore
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Farmer
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage; D000818:Animals; D003243:Consciousness; D004285:Dogs; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005934:Glucagon / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D019518:Postprandial Period / Q000187:drug effects*; D018027:Receptors, Glucagon / Q000819:agonists; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D000082:Acetaminophen; D005934:Glucagon; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; C000593833:GLP1R protein, human; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: hepatic glucose metabolism; mixed meal; type 2 diabetes