title: 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside renders glucose output by the liver of the dog insensitive to a pharmacological increment in insulin.
abstract: This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-beta-d-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before study. Protocols consisted of equilibration (-130 to -30 min), basal (-30 to 0 min), and hyperinsulinemic-euglycemic (0-150 min) periods. At time (t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU.kg(-1).min(-1). At t = 60 min, 1 mg.kg(-1).min(-1) portal venous 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose approximately 9- and approximately 27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 +/- 0.5 and 2.0 +/- 0.5 mg.kg(-1).min(-1) in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, Ser(79)) phosphorylation in INS2. Hepatic ACC (Ser(79)) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked.
authors.affiliation: Dept. of Molecular Physiology and Biophysics, Duiabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, TN, USA. rcamacho@aecom.yu.edu
authors.forename: Raul C
authors.initials: RC
authors.lastname: Camacho
authors.forename: D Brooks
authors.initials: DB
authors.lastname: Lacy
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001158:Arteries; D001786:Blood Glucose / Q000032:analysis; D004285:Dogs; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000032:analysis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose