Effect of AMPK activation on muscle glucose metabolism in conscious rats

The effect of AMP-activated protein kinase (AMPK) activation on skeletal mu scle glucose metabolism was examined in awake rats by infusing them with 5- aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR; 40 mg/kg bolus and 7.5 mg.kg(-1).min(-1) constant infusion) along with a variable infusio n of glucose (49.1 +/- 2.4 mu mol.kg(-1).min(-1)) to maintain euglycemia. A ctivation of AMPK by AICAR caused 2-deoxy-D-[1,2-H-3]glucose (2-DG) uptake to increase more than twofold in the soleus and the lateral and medial gast rocnemius compared with saline infusion and occurred without phosphatidylin ositol 3-kinase activation. Glucose uptake was also assessed in vitro by us e of the epitrochlearis muscle incubated either with AICAR (0.5 mM) or insu lin (20 mU/ml) or both in the presence or absence of wortmannin (1.0 mu M). AICAR and insulin increased muscle 2-DG uptake rates by similar to 2- and 2.7-fold, respectively, compared with basal rates. Combining AICAR and insu lin led to a fully additive effect on muscle glucose transport activity. Wo rtmannin inhibited insulin-stimulated glucose uptake. However, neither wart mannin nor 8-(p-sulfophenyl)-theophylline (10 mu M), an adenosine receptor antagonist, inhibited the AICAR-induced activation of glucose uptake. Elect rical stimulation led to an about threefold increase in glucose uptake over basal rates, whereas no additive effect was found when AICAR and contracti ons were combined. In conclusion, the activation of AMPK by AICAR increases skeletal muscle glucose transport activity both in vivo and in vitro. This cellular pathway may play an important role in exercise-induced increase i n glucose transport activity.