5-Amino-Imidazole Carboxamide Riboside Increases Glucose Transport and Cell-Surface GLUT4 Content in Skeletal Muscle From Subjects With Type 2 Diabetes
- Heikki A. Koistinen123,
- Dana Galuska4,
- Alexander V. Chibalin1,
- Jing Yang5,
- Juleen R. Zierath1,
- Geoffrey D. Holman5 and
- Harriet Wallberg-Henriksson12
- 1Department of Surgical Sciences, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
- 2Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
- 3Biomedicum, Helsinki, Finland
- 4Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- 5Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
Abstract
AMP-activated protein kinase (AMPK) activation by AICAR (5-amino-imidazole carboxamide riboside) is correlated with increased glucose transport in rodent skeletal muscle via an insulin-independent pathway. We determined in vitro effects of insulin and/or AICAR exposure on glucose transport and cell-surface GLUT4 content in skeletal muscle from nondiabetic men and men with type 2 diabetes. AICAR increased glucose transport in a dose-dependent manner in healthy subjects. Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects. In contrast, insulin- and AICAR-stimulated responses on glucose transport and cell-surface GLUT4 content were impaired in subjects with type 2 diabetes. Importantly, exposure of type 2 diabetic skeletal muscle to a combination of insulin and AICAR increased glucose transport and cell-surface GLUT4 content to levels achieved in control subjects. AICAR increased AMPK and acetyl-CoA carboxylase phosphorylation to a similar extent in skeletal muscle from subjects with type 2 diabetes and nondiabetic subjects. Our studies highlight the potential importance of AMPK-dependent pathways in the regulation of GLUT4 and glucose transport activity in insulin-resistant skeletal muscle. Activation of AMPK is an attractive strategy to enhance glucose transport through increased cell surface GLUT4 content in insulin-resistant skeletal muscle.
Footnotes
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Address correspondence and reprint requests to Juleen R. Zierath, Department of Clinical Physiology and Integrative Physiology, Karolinska Institutet, von Eulers väg 4, II tr, SE-171 77 Stockholm, Sweden. E-mail: Juleen.Zierath{at}fyfa.ki.se.
Received for publication 28 November 2002 and accepted in revised form 27 January 2003.
ACC, acetyl-CoA carboxylase; AICAR, 5-amino-imidazole carboxamide riboside; AMPK, AMP-activated protein kinase; KHB, Krebs-Henseleit buffer; MAPK, mitogen-activated protein kinase; Vo2max, maximal oxygen uptake.
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