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Diabetes 50:12-17, 2001
© 2001 by the American Diabetes Association, Inc.

Chronic Treatment With 5-Aminoimidazole-4-Carboxamide-1-ß-D-Ribofuranoside Increases Insulin-Stimulated Glucose Uptake and GLUT4 Translocation in Rat Skeletal Muscles in a Fiber Type—Specific Manner

Esben S. Buhl, Niels Jessen, Ole Schmitz, Steen B. Pedersen, Oluf Pedersen, Geoffrey D. Holman, and Sten Lund

From the Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes) (E.S.B., N.J., O.S., S.L.), Aarhus Kommune-hospital; the Department of Endocrinology and Internal Medicine (S.B.P.), Aarhus Amtssygehus, Aarhus University Hospital; the Institute of Clinical Pharmacology (O.S.), University of Aarhus, Aarhus; the Steno Diabetes Centre and Hagedorn Research Institute (O.P.), Gentofte, Copenhagen, Denmark; and the Department of Biology and Biochemistry (G.D.H.), University of Bath, Claverton Down, U.K.

Address correspondence and reprint requests to Sten Lund, MD, Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark. E-mail: sl{at}dadlnet.dk .

Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside), an activator of the AMP-activated protein kinase, increases hexokinase activity and the contents of total GLUT4 and glycogen in rat skeletal muscles. To explore whether AICAR also affects insulin-stimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt). Maximally insulin-stimulated (60 nmol/l) glucose uptake was markedly increased in epitrochlearis (EPI) muscle (average 63%, P < 0.001, n = 18-19) and in extensor digitorum longus muscle (average 26%, P < 0.001, n = 26-30). In contrast, administration of AICAR did not maximally influence insulin-stimulated glucose transport in soleus muscle. Studies of EPI muscle with the 4,4'-O-[2-[2-[2-[2-[2-[6-(biotinylamino)hexanoyl]amino]ethoxy]ethoxy]ethoxy]-4-(1-azi-2,2,2,-trifluoroethyl)benzoyl]amino-1,3-propanediyl]bis-D-mannose photolabeling technique showed a concomitant increase (average 68%, P < 0.02) in cell surface GLUT4 content after insulin exposure in AICAR-injected rats when compared with controls. In conclusion, 5 days of AICAR administration induces a pronounced fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI). These results are comparable with the effects of chronic exercise training, and it brings the AMP-activated protein kinase into focus as a new interesting target for future pharmacological intervention in insulin-resistant conditions.

Abbreviations: 3-OMG, 3-O-methylglucose; AEBSF, 4-(2-aminoethyl)-benzenesulfonyl fluoride, hydrochloride; AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; AMPK, AMP-activated protein kinase; Bio-LC-ATB-BMPA, 4,4'-O-[2-[2-[2-[2-[2-[6-(biotinylamino) hexanoyl]amino]ethoxy]ethoxy]ethoxy]-4-(1-azi-2,2,2,-trifluoroethyl)benzoyl]amino-1,3-propanediyl]bis-D-mannose; BSA, bovine serum albumin; EDL, extensor digitorum longus; EPI, epitrochlearis; FG, fast-twitch glycolytic; FOG, fast-twitch oxidative glycolytic; HES, hetastarch in saline; KHBB, Krebs-Henseleit bicarbonate buffer; LCFA, long-chain fatty acid; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; RG, red part of the gastrocnemius; SO, slow oxidative; WG, white part of the gastrocnemius


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