Persistent hyperinsulinemia contributes to peripheral insulin resistance by a variety of mechanisms, including decreasing insulin receptor expression and altering intracellular signaling cascades, i.e., inhibition of insulin receptor (IR) kinase activity [11,12] and insulin receptor substrates-1 and -2 (IRS1/2) tyrosine phosphorylation, increasing IRS1/2 proteasome-mediated degradation [13,14], phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation of IRS1/2 [15,16]. The gene discussed is INSR; the disease is hyperinsulinism.