TNF and Hyperglycemia: TNF-α could be importantly contributing to the development of IR by inhibition and degradation of the IRS mediated by a serine phosphorylation through different mechanisms: (1) SOCS3 is induced by the NFκB/JNK-mediated activation of TNF-α and IL-6 [81], or via CEBPA activation [82], inducing ubiquitin-mediated degradation of IRS1 and IRS2 [83]; (2) MTOR can be activated by TNF-α or PKCβ pathways [84,85] due to hyperglycemia, leading to phosphorylation of multiple serine residues in IRS1 and IRS2 with their further degradation; (3) JNK1 promotes IRS1 and IRS2 serine phosphorylation [86,87].