In vitro, acute insulin signaling activated eNOS phosphorylation mediated by PI3K/Akt signaling in LECs, but prolonged hyperinsulinemia and hyperglycemia promoted insulin resistance, impaired PI3K/Akt/eNOS signaling, mitochondrial function, and NO bioavailability, and also increased lymphatic permeability. Here, AKT1 is linked to Insulin resistance.