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

doi:10.2337/diabetes.50.1.12

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

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 .

Abstract

Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide-1-β-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.