Direct inhibition by angiotensin II of insulin‐dependent glucose transport activity in mammalian skeletal muscle involves a ROS‐dependent mechanism

Abstract

Angiotensin II (Ang II) is elevated in hypertension and impairs insulin signaling and insulin‐stimulated glucose transport activity in muscle cell lines. No previous study has directly investigated how Ang II impacts insulin action in isolated mammalian skeletal muscle. We investigated the molecular actions of Ang II on insulin signaling and glucose transport activity in isolated skeletal muscle from female lean Zucker rats. Soleus strips were incubated with insulin (5 mU/ml) and/or Ang II (500 nM) for 2 hr. Ang II alone did not affect glucose transport or distal insulin signaling (Akt and glycogen synthase kinase‐3β (GSK‐3β)). Ang II inhibited insulin‐stimulated glucose transport (39%) and decreased phosphorylation of Akt Ser473 (37%) and GSK‐3β Ser9 (42%). Ang II did not affect phosphorylation of IRS‐1 Ser307 or p38 MAPK. We used the superoxide dismutase mimetic, tempol (1 mM), to determine if reactive oxygen species (ROS) contribute to Ang II‐mediated insulin resistance. Tempol partially reversed (42%) the Ang II‐induced inhibition of insulin‐stimulated glucose transport. These results indicate that Ang II inhibits distal insulin signaling and insulin‐stimulated glucose transport activity in isolated mammalian skeletal muscle, and this effect is partially mediated by ROS. Ang II may represent a factor that contributes to the etiology of both hypertension and insulin resistance in skeletal muscle.