IRS1 and Insulin resistance: The acute activation of Akt appears to increase glucose uptake, predominantly through enhanced sarcolemmal GLUT4 localization [38], while its chronic activation leads to insulin resistance, with a substantial decrease in GLUT4 both in the intracellular cytosol and on the sarcolemal membrane, in addition to negative feedback inhibition of IRS-1-PI3K coupling [40, 45].