INS and Hyperinsulinemia: Several factors including the oxidative stress, the neuro-hormonal stimulation, and the hyperinsulinemia have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of insulin receptor and of its substrates (Fig. 2); these include the proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation [71].