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United States Department of Agriculture

Agricultural Research Service

Research Project: THE ROLE OF B VITAMINS AND ONE CARBON METABOLISM IN AGING Title: Methotrexate increases skeletal muscle GLUT4 expression and improves metabolic control in experimental diabetes

Authors
item Russo, Giuseppina -
item Minutoli, Letteria -
item Bitto, Alessandra -
item Altavilla, Domenica -
item Alessi, Eugenio -
item Giandalia, Annalisa -
item Romeo, Elisabetta -
item Stagno, Maria -
item Squadrito, Francesco -
item Cucinotta, Domenico -
item Selhub, Jacob -

Submitted to: Journal of Nutrition and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 14, 2012
Publication Date: June 13, 2012
Citation: Russo, G., Minutoli, L., Bitto, A., Altavilla, D., Alessi, E., Giandalia, A., Romeo, E.L., Stagno, M.F., Squadrito, F., Cucinotta, D., Selhub, J. 2012. Methotrexate increases skeletal muscle GLUT4 expression and improves metabolic control in experimental diabetes. Journal of Nutrition and Metabolism. DOI:10.1155/2012/132056.

Interpretive Summary: Methotrexate (MTX) is a drug which resembles folic acid in structure but differs in a way that it causes it to be a strong inhibitor of folate metabolism to the extent that it is used at high concentrations in chemotherapy. At low concentrations MTX was found very effective against autoimmune diseases such as rheumatoid arthritis and Lupus disease. The action mechanism of low dose MTX differs from the high doses that are used for chemotherapy. Therefore in the present study we studied the effect of low dose MTX on mice that are genetically predispose to be fat and acquire diabetes. Our data have shown that low dose MTX is causes blood glucose to be lower, insulin to be lower and the protein which is responsible for transporting glucose into the cell is increased significantly. This suggests that low dose MTX could be effective in treating people with metabolic syndrome (a combination of medical disorders, most typically characterized by persons with a body mass index over 30, putting them in the ‘obese’ range).

Technical Abstract: 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-m(+)/(+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+)/(+)m). In the db(+)/db(+) mice, MTX treatment was associated with an approximate 2-fold increase in skeletal muscle GLUT4 protein concentration and a >4-fold increase in GLUT4 mRNA expression (P < 0.01, 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 < 0.001), and glucose levels only (P < 0.05) in controls. These data indicate a different route to increase skeletal muscle GLUT4 expression, through the potential inhibition of the enzyme AICAR transformylase.

Last Modified: 12/21/2014
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