Characterization of the adenosine receptor modulating insulin action in rat skeletal muscle

The pharmacological profile of adenosine receptors in rat soleus muscle has been investigated by studying the effects of A1-and A2-selective adenosine receptor agonists on glucose utilization and the system A amino acid transporter under conditions where adenosine has been reported to exert a modulatory action on these insulin-sensitive processes. In the presence of adenosine deaminase and a sub-maximally effective concentration of insulin (50 microU/ml), the A1-selective agonists N6-cyclopentyladenosine and R(-)-N6-(2-phenylisopropyl)adenosine (R(-)PIA) caused concentration-dependent inhibitions of 2-deoxy[3H]glucose 6-phosphate and alpha-[14C]methylaminoisobutyric acid accumulations, but had no effect on the rate of [14C]glucose incorporation into glycogen, in incubated soleus muscle strips. These effects on glucose transport/phosphorylation and system A amino acid transport could be antagonized by 8-cyclopentyl-1,3- dipropylxanthine and 8-phenyltheophylline. The A2-selective adenosine receptor agonists CGS 21680 and 2-(phenylamino)adenosine were much less potent in their inhibition of these metabolic processes. These data support the proposal that adenosine exerts a post-receptor insulin-modulatory action in skeletal muscle and strongly suggest that this action is mediated by A1 adenosine receptors: the possible intracellular signalling mechanism(s) for this hormone-modulatory effect of adenosine are discussed.