5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside causes acute hepatic insulin resistance in vivo

R. Richard Pencek, Jane Shearer, Raul C. Camacho, Freyja D. James, D. Brooks Lacy, Patrick T. Fueger, E. Patrick Donahue, Wanda Snead, David H. Wasserman

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31 Scopus citations

Abstract

The infusion of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) causes a rise in tissue concentrations of the AMP analog 5-aminoimidazole-4-carboxamide-1-β-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.

Original languageEnglish (US)
Pages (from-to)355-360
Number of pages6
JournalDiabetes
Volume54
Issue number2
DOIs
StatePublished - Feb 1 2005

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Pencek, R. R., Shearer, J., Camacho, R. C., James, F. D., Lacy, D. B., Fueger, P. T., Donahue, E. P., Snead, W., & Wasserman, D. H. (2005). 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside causes acute hepatic insulin resistance in vivo. Diabetes, 54(2), 355-360. https://doi.org/10.2337/diabetes.54.2.355