IRS1 and hyperinsulinism: There are various mechanisms of chronic hyperinsulinemia contributing to peripheral IR, such as down expression of insulin receptors and changes in signaling cascades, including the inhibition of insulin receptor kinase activity and tyrosine phosphorylation of insulin receptor substrates-1 and -2 (IRS1/2), enhancement of IRS1/2 proteasome-mediated degradation, phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation [89].