The principal findings of our study are that (1) DEX-mediated GR and GRα association with PI3K inhibits the association of PI3K with pIRS1 in skeletal muscle and this may contribute to development of insulin resistance, and (2) Treatment with HGSD improves insulin resistance through decreased association of GR and GRα with PI3K and subsequently increased association of PI3K with IRS1. Here, IRS1 is linked to Insulin resistance.