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5-Aminoimidazole-4-Carboxamide-1-ß-D-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

¹ Hormone and Metabolic Research Unit, School of Medicine, Université catholique de Louvain and Institute of Cellular Pathology, Brussels, Belgium
² Division of Cardiology, School of Medicine, Université catholique de Louvain, Brussels, Belgium
³ Bioénergétique Fondamentale et Appliquée Institut National de la Santé et de la Recherche Medicalé (INSERM) EMI0221, Université J. Fourier, Grenoble, France
⁴ Institut Cochin, INSERM U567, Département d’Endocrinologie, Métabolisme et Cancer, Université René Descartes Paris 5, Centre national de La Recherche Scientifique, Paris, France
⁵ Merck-Santé, Lyon, France

Address correspondence and reprint requests to Dr. Bruno Guigas, Hormone and Metabolic Research Unit, Institute of Cellular Pathology, UCL 7529, avenue Hippocrate 75, 1200 Brussels, Belgium. E-mail: bruno.guigas{at}horm.ucl.ac.be

Abbreviations: ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; AMPK, AMP-activated protein kinase; FBPase-2, fructose-2,6-bisphosphatase; Fru-1-P, fructose 1-phosphate; Fru-6-P, fructose 6-phosphate; Fru-2,6-P₂, fructose 2,6-bisphosphate; G6Pase, glucose-6-phosphatase; GKRP, glucokinase regulatory protein; Glc-6-P, glucose 6-phosphate; HBM, hepatocyte basal medium; PFK, 6-phosphofructokinase; PKA, protein kinase A; PKB, protein kinase B

AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver ₁ and ₂ AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions.

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