IRS1 and Hyperglycemia: Research has shown that neddylation modification is involved in IRS1 and IRS2-dependent insulin signaling, and inhibition of neddylation with MLN4924, an NAE inhibitor, can rapidly decrease hepatic glucose generationand alleviate hyperglycemia in mice through the activation of IRS1 and IRS2 as well as the PI3K/AKT signaling pathway[39, 40].