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5-Aminoimidazole-4-Carboxamide 1-ß-D-Ribofuranoside Acutely Stimulates Skeletal Muscle 2-Deoxyglucose Uptake in Healthy Men

¹ Department of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
² School of Life Sciences, Heriot Watt University, Edinburgh, Scotland
³ Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, Scotland
⁴ College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, Scotland
⁵ Department of Pharmacology and Neurosciences, University of Dundee, Dundee, Scotland
⁶ School of Biomedical Sciences, Graduate Entry Medical School, University of Nottingham, Derby City Hospital, Derby, U.K

Address correspondence and reprint requests to Dr. Daniel Cuthbertson, Department of Medicine, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY. E-mail: d.j.r.cuthbertson{at}dundee.ac.uk

Abbreviations: 2DG, 2-deoxyglucose; 2DG6P, 2-deoxyglucose 6-phosphate; ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside; AMPK, AMP-activated protein kinase; aPKC, atypical protein kinase C; ERK, extracellular signal–regulated kinase; FDG, fluorodeoxyglucose; GS, glycogen synthase; GSK, glycogen synthase kinase; IRS-1, insulin receptor substrate-1; PKB, protein kinase B; ZMP, 5-aminoimidazole-4-carboxamide ribonucleoside

Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 ± 8 years, BMI 25 ± 4 kg/m² [mean ± SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R² = 0.88 ± 0.09). After 3 h, 2DG uptake increased 2.1 ± 0.8- and 4.7 ± 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK ₁ and ₂ activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal–regulated kinase 1/2, but phosphorylation of ß-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 ± 0.6 to 10 ± 0.6 mg · kg^–1 · min^–1 (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.

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