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Diabetes 53:3074-3081, 2004
© 2004 by the American Diabetes Association, Inc.

The {alpha}2–5'AMP-Activated Protein Kinase Is a Site 2 Glycogen Synthase Kinase in Skeletal Muscle and Is Responsive to Glucose Loading

Sebastian B. Jørgensen1, Jakob N. Nielsen1, Jesper B. Birk1, Grith Skytte Olsen3, Benoit Viollet4, Fabrizio Andreelli4, Peter Schjerling2, Sophie Vaulont4, D. Grahame Hardie5, Bo F. Hansen3, Erik A. Richter1, and Jørgen F.P. Wojtaszewski1

1 Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
2 Department for Molecular Muscle Biology, Rigshospitalet, Copenhagen, Denmark
3 Diabetes Biology, Novo Nordisk, Maaloev, Denmark
4 Department of Genetic, Development, and Molecular Pathology, Institut Cochin, INSERM, CNRS, Rene Descartes University, Paris, France
5 Division of Molecular Physiology, Faculty of Life Sciences, Dundee University, Dundee, Scotland

The 5'AMP-activated protein kinase (AMPK) is a potential antidiabetic drug target. Here we show that the pharmacological activation of AMPK by 5-aminoimidazole-1-ß-4-carboxamide ribofuranoside (AICAR) leads to inactivation of glycogen synthase (GS) and phosphorylation of GS at Ser 7 (site 2). In muscle of mice with targeted deletion of the {alpha}2-AMPK gene, phosphorylation of GS site 2 was decreased under basal conditions and unchanged by AICAR treatment. In contrast, in {alpha}1-AMPK knockout mice, the response to AICAR was normal. Fuel surplus (glucose loading) decreased AMPK activation by AICAR, but the phosphorylation of the downstream targets acetyl-CoA carboxylase-ß and GS was normal. Fractionation studies suggest that this suppression of AMPK activation was not a direct consequence of AMPK association with membranes or glycogen, because AMPK was phosphorylated to a greater extent in response to AICAR in the membrane/glycogen fraction than in the cytosolic fraction. Thus, the downstream action of AMPK in response to AICAR was unaffected by glucose loading, whereas the action of the kinase upstream of AMPK, as judged by AMPK phosphorylation, was decreased. The fact that {alpha}2-AMPK is a GS kinase that inactivates GS while simultaneously activating glucose transport suggests that a balanced view on the suitability for AMPK as an antidiabetic drug target should be taken.

Address correspondence and reprint requests to Jørgen F.P. Wojtaszewski, PhD, Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sport Sciences, 13 Universitetsparken, University of Copenhagen, DK-2100 Copenhagen, Denmark. E-mail: jwojtaszewski{at}aki.ku.dk


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.