INS and Insulin resistance: Firstly, insulin signaling molecules were directly targeted by E3 ubiquitin ligases, such as mitsugumin 53 (MG53) (154), CRL7 (155), Cbl proteins (156, 157), suppressors of cytokine signaling (SOCS) 1/3 (158), Fbxo40 (159), murine double minute 2 (MDM2) (160), NEDD4 (161, 162), and TRIM32 (163), which are known to be involved in the ubiquitin-dependent degradation of key insulin signaling molecules, including PI3K, AKT, IR, and IRS, contributed to insulin resistance.