5-Amino-Imidazole Carboxamide Riboside Increases Glucose Transport and Cell-Surface GLUT4 Content in Skeletal Muscle From Subjects With Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 5; pp. 1066 - 1072
• Main Authors: Koistinen, Heikki A., Galuska, Dana, Chibalin, Alexander V., Yang, Jing, Zierath, Juleen R., Holman, Geoffrey D., Wallberg-Henriksson, Harriet
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2003
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - therapeutic use; Biological and medical sciences; Biological Transport - drug effects; Body Mass Index; Development and progression; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glucose Transporter Type 4; Humans; Hypoglycemic Agents - therapeutic use; In Vitro Techniques; Insulin - therapeutic use; Insulin resistance; Middle Aged; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Muscle, Skeletal - metabolism; Oxygen Consumption - drug effects; Physiological aspects; Reference Values; Ribonucleotides - therapeutic use; Type 2 diabetes; Sweden
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.5.1066

5-Amino-Imidazole Carboxamide Riboside Increases Glucose Transport and Cell-Surface GLUT4 Content in Skeletal Muscle From Subjects With Type 2 Diabetes Heikki A. Koistinen 1 2 3 , Dana Galuska 4 , Alexander V. Chibalin 1 , Jing Yang 5 , Juleen R. Zierath 1 , Geoffrey D. Holman 5 and Harriet Wallberg-Henriksson 1 2 1 Department of Surgical Sciences, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden 2 Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland 3 Biomedicum, Helsinki, Finland 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 5 Department 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 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; V o 2max , maximal oxygen uptake. DIABETES