INS and hyperinsulinism: During a state of insulin resistance and hyperinsulinemia, the metabolic PI3K/AKT pathway is down-regulated, due to Ser/Thr phosphorylation of IRS by PKC and inflammatory kinases, such as IKKß and indeed JNK, which impedes insulin-induced IRS tyrosine phosphorylation [78,79], and the effect of SOCS, which also impede IRS tyrosine phosphorylation [80].