Peptide IPPKKNQDKTE ameliorates insulin resistance in HepG2 cells via blocking ROS-mediated MAPK signaling

Reactive oxygen species (ROS) has been found to play an important role in insulin resistance. Whether the improvement effects of the peptide IPPKKNQDKTE on hepatic insulin resistance were mediated by ROS elimination was examined in this study. Results showed that the high glucose-induced MAPK signaling activation was inhibited by IPPKKNQDKTE in insulin-resistant HepG2 cells, which contributed to the improvement of IPPKKNQDKTE on cellular glucose uptake and the phosphorylation levels of insulin receptor substrate-1 (IRS-1) Ser636/639 and Ser307. IPPKKNQDKTE dose-dependently reduced high glucose-induced ROS production, which involved in suppression of IPPKKNQDKTE on MAPK signaling in high glucose-induced insulin-resistant HepG2 cells. Moreover, IPPKKNQDKTE increased Nrf2 nucleus translocation and induced HO-1 expression. HO-1 inhibitor partly reversed IPPKKNQDKTE-mediated suppression on high glucose-induced ROS production. Taken together, IPPKKNQDKTE reduced high glucose-induced ROS production and MAPK activation by the activation of Nrf2/HO-1, which contributed to increase the glucose uptake and decrease the Ser phosphorylation levels of IRS-1 in insulin-resistant HepG2 cells. These results indicated that IPPKKNQDKTE plays a potential role in the management of hepatic insulin resistance.