Cytokines, fatty acids, hyperglycemia, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and insulin induce inhibitory Ser/Thr phosphorylation of IR, notably IRS-1 and -2, via JNK, IKK, traditional and novel PKCs, mTORC1/S6K, and MAPK [6,47,116]. Here, IRS1 is linked to Hyperglycemia.