The role of beta-adrenergic receptors in regulating skeletal muscle glucose utilization at rest and during exercise

Epinephrine working via β-adrenergic receptors can antagonize glucose utilization by skeletal muscle at rest and during exercise. The effects of epinephrine on the metabolism of glucose in the fast-twitch (epitrochlearis) and the slow-twitch (soleus) muscle were investigated at rest and during muscle contraction in the presence of a physiological concentration of insulin. In addition, the effect of β-adrenergic receptor downregulation on the inhibition of glucose uptake by epinephrine was investigated. Using radioactively labeled glucose analogs, it was determined that the attenuation in insulin-stimulated glucose utilization at rest was due to the attenuation in glucose transport as well as phosphorylation. The inhibition of insulin-stimulated glucose transport and uptake corresponded to a reduction in IRS-1/PI 3-kinase activity and an increase in the intracellular concentration of glucose-6-phosphate. Downregulation of β-adrenergic receptors with constant exposure to clenbuterol, a β-adrenergic receptor agonist, or blocking β-adrenergic receptors with propranolol, a β-adrenergic receptor antagonist, prevented the inhibition of insulin-stimulated glucose uptake by epinephrine. Epinephrine also attenuated the additive effect of insulin and contraction on glucose uptake. The reduction in insulin/contraction-stimulated glucose uptake resulted in a glucose uptake rate similar to contraction alone. This suppression of glucose uptake by epinephrine was accompanied by a decrease in IRS-1/PI 3-kinase activity, while no augmenting effect was observed on the intracellular concentration of glucose-6-phosphate. In the presence of propranolol, epinephrine was ineffective in antagonizing insulin/contraction-stimulated glucose uptake in skeletal muscle. These findings suggest that epinephrine can regulate insulin-stimulated glucose uptake during contraction independent of glucose-6-phosphate concentrations. They also indicate that epinephrine may play a significant role in regulating muscle glucose uptake during muscle contraction by modulating insulin-stimulated glucose transport. Collectively, these findings suggest that epinephrine is capable of regulating insulin-stimulated glucose utilization, activated by a physiological insulin concentration at rest and during muscle contraction, by inhibiting glucose transport. The regulation of glucose utilization by epinephrine at the glucose transport step instead of a point distal to transport would limit glucose utilization while protecting the muscle cell from an excessive accumulation of intracellular free glucose.