title: 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside causes acute hepatic insulin resistance in vivo.
abstract: The infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) causes a rise in tissue concentrations of the AMP analog 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranotide (ZMP), which mimics an elevation of cellular AMP levels. The purpose of this work was to determine the effect of raising hepatic ZMP levels on hepatic insulin action in vivo. Dogs had sampling and infusion catheters as well as flow probes implanted 16 days before an experiment. After an 18-h fast, blood glucose was 82 +/- 1 mg/dl and basal net hepatic glucose output 1.5 +/- 0.2 mg . kg(-1) . min(-1). Dogs received portal venous glucose (3.2 mg . kg(-1) . min(-1)), peripheral venous somatostatin, and basal portal venous glucagon infusions from -90 to 60 min. Physiological hyperinsulinemia was established with a portal insulin infusion (1.2 mU . kg(-1) . min(-1)). Peripheral venous glucose infusion was used to clamp arterial blood glucose at 150 mg/dl. Starting at t = 0 min, dogs received portal venous AICAR infusions of 0, 1, or 2 mg . kg(-1) . min(-1). Net hepatic glucose uptake was 2.4 +/- 0.5 mg . kg(-1) . min(-1) (mean of all groups) before t = 0 min. In the absence of AICAR, net hepatic glucose uptake was 1.9 +/- 0.4 mg . kg(-1) . min(-1) at t = 60 min. The lower-dose AICAR infusion caused a complete suppression of net hepatic glucose uptake (-1.0 +/- 1.7 mg . kg(-1) . min(-1) at t = 60 min). The higher AICAR dose resulted in a profound shift in hepatic glucose balance from net uptake to a marked net output (-6.1 +/- 1.9 mg . kg(-1) . min(-1) at t = 60 min), even in the face of hyperglycemia and hyperinsulinemia. These data show that elevations in hepatic ZMP concentrations, induced by portal venous AICAR infusion, cause acute hepatic insulin resistance. These findings have important implications for the targeting of AMP kinase for the treatment of insulin resistance, using AMP analogs.
authors.affiliation: Department of Molecular Physiology and Biophysics, Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA. pencekr@dom.pitt.edu
authors.forename: R Richard
authors.initials: RR
authors.lastname: Pencek
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
authors.forename: Raul C
authors.initials: RC
authors.lastname: Camacho
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.forename: D Brooks
authors.initials: DB
authors.lastname: Lacy
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.forename: Wanda
authors.initials: W
authors.lastname: Snead
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D015309:Glucose Clamp Technique; D006019:Glycolysis / Q000187:drug effects; D006946:Hyperinsulinism / Q000097:blood; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018408:Patch-Clamp Techniques; D011169:Portal Vein / Q000502:physiology; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000242:Cyclic AMP; C031143:AICA ribonucleotide