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Journal of Nutrition and Metabolism
Volume 2012 (2012), Article ID 132056, 7 pages
Research Article

Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes

1Department of Internal Medicine, University of Messina, 98122 Messina, Italy
2Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, 98122 Messina, Italy
3Vitamin Bioavailability Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA

Received 13 January 2012; Revised 10 March 2012; Accepted 14 April 2012

Academic Editor: Aron Troen

Copyright © 2012 Giuseppina T. Russo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue concentrations can be increased, in vivo, by low doses of methotrexate (MTX) through the inhibition of the enzyme AICAR transformylase. We report here the first evidence that, in experimental type 2 diabetes, chronic treatment with low doses of MTX increases skeletal muscle GLUT4 expression and improves metabolic control. MTX (0.5 mg/kg body weight) or vehicle was administered intraperitoneally, once a week for 4 weeks, to genetically diabetic female C57BL/KsJ- π‘š + / + 𝐿 𝑒 𝑝 𝑑 𝑑 𝑏 mice ( 𝑑 𝑏 + / 𝑑 𝑏 + ) and their normoglycemic littermates ( 𝑑 𝑏 + / + π‘š ). In the 𝑑 𝑏 + / 𝑑 𝑏 + mice, MTX treatment was associated with a ~2-fold increase in skeletal muscle GLUT4 protein concentration and a >4-fold increase in GLUT4 mRNA expression ( 𝑃 < 0 . 0 1 , all), as compared to vehicle-treated mice; no significant differences were noted in controls. MTX treatment was also associated with a significant reduction of glucose and insulin serum concentrations in diabetic mice ( 𝑃 < 0 . 0 0 1 ), and glucose levels only ( 𝑃 < 0 . 0 5 ) in controls. These data indicate a different route to increase skeletal muscle GLUT4 expression, through the potential inhibition of the enzyme AICAR transformylase.