Antagonism of endocannabinoid receptor CB1 directly increases basal and insulin‐stimulated glucose transport activity in soleus muscle of lean Zucker rats

Abstract

The endocannabinoid system is emerging as a new pharmacological target in the treatment of obesity and insulin resistance. It is known that endocannabinoid receptors (CB1 subtype) are expressed in rat skeletal muscle. However, it is currently unknown what role, if any, modulation of these receptors might have on the glucose transport system in skeletal muscle. Therefore, the goal of this study was to determine whether glucose transport activity in soleus muscle of lean Zucker rats is directly affected by selective CB1 receptor inhibition. Soleus muscle strips from lean Zucker rats were incubated for 60 min in the absence or presence of a maximally‐effective insulin concentration (5 mU/ml) and increasing concentrations (25–1000 nM) of the CB1 receptor antagonist, SR 141716. In the absence of insulin, SR141716 at 100–200 nM activated glucose transport (2‐deoxyglucose uptake) by 33% (p<0.05), with an EC50 of ~50 nM. Insulin‐stimulated glucose transport was enhanced 37% (p<0.05) by 100 nM SR141716, again with an EC50 of ~50 nM. These SR141716‐mediated increases were substantially reduced at the highest concentrations of the CB1 receptor antagonist. These results support the hypothesis that the glucose transport system in rat skeletal muscle is directly and positively modulated by CB1 receptor antagonism.