5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes

Incubation of skeletal muscle with 5-aminoimidazole-4-carboxamide ribonucle oside (AICAR), a compound that activates 5'-AMP-activated protein kinase (A MPK), has been demonstrated to stimulate glucose transport and GLUT4 transl ocation to the plasma membrane. In this study, we characterized the AMPK ca scade in 3T3-L1 adipocytes and the response of glucose transport to incubat ion with AICAR, Both isoforms of the catalytic alpha-subunit of AMPK are ex pressed in 3T3-L1 adipocytes, in which AICAR stimulated AMPK( activity in a time- and dose-dependent fashion. AICAR stimulated 8-deoxy-D-glucose trans port twofold and reduced insulin-stimulated uptake to 62% of the control tr ansport rate dose-dependently, closely correlating with the activation of A MPK. AICAR also inhibited insulin-stimulated GLUT4 translocation, assessed using the plasma membrane lawn assay. The effects of AICAR on insulin-stimu lated glucose transport are not mediated by either adenosine receptors or n itric oxide synthase and are mediated downstream of phosphatidylinositol 3' -kinase stimulation. We propose that in contrast to skeletal muscle, in whi ch AMPK stimulation promotes glucose transport to provide ATP as a fuel, AM PK stimulation inhibits insulin-stimulated glucose transport in adipocytes, inhibiting triacylglycerol synthesis, to conserve ATP under conditions of cellular stress. Investigation of the mode of action of AICAR and AMPK may, therefore, give insight into the mechanism of insulin action.