4‐Methylesculetin Ameliorates Hepatic Insulin Resistance in HepG2 Cells Through AMPK/FOXO1, PI3K/AKT/GSK3 β Pathways and SIRT1/NOX4 Axis

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BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by elevated blood glucose. OBJECTIVE: This study is aimed at evaluating the efficacy of 4-methylesculetin in mitigating insulin resistance (IR) in HepG2 cells, thereby identifying the underlying mechanisms. METHODS: An HepG2 cell insulin resistance (IR-HepG2) model was established using high glucose and high insulin. Cell viability was evaluated via the CCK-8 test to ascertain the safety dosage, whereas the impact of 4-methylesculetin on glucose metabolism was investigated by quantifying glucose uptake and glycogen levels. The impact of 4-methylesculetin on oxidative stress within the IR-HepG2 model was assessed through the analysis of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX). To investigate the underlying mechanisms, Western blot analysis was performed to determine the protein expression levels of key molecules involved in insulin signaling and oxidative stress, including p-AMPK, AMPK, SIRT1, NOX4, p-AKT, AKT, p-GSK3β, GSK3β, p-FOXO1, FOXO1, p-GYS1, GYS1, PEPCK, GLUT2, and G6Pase. RESULTS: In the IR-HepG2 model, 4-methylesculetin treatment significantly enhanced glucose consumption and glycogen synthesis (p < 0.01). It also markedly alleviated oxidative stress by increasing the activities of antioxidant enzymes SOD and GSH-PX (p < 0.05 or p < 0.01), and reducing the levels of ROS and MDA (p < 0.01). Western blot analysis revealed that these beneficial effects were mediated through the activation of the AMPK/FOXO1 and PI3K/AKT/GSK3β pathways, as well as the activation of SIRT1, which led to the suppression of NOX4. CONCLUSIONS: 4-Methylesculetin may ameliorate IR in HepG2 cells by improving glucose metabolism via AMPK/FOXO1 and PI3K/AKT/GSK3β pathways and attenuating oxidative stress via SIRT1/NOX4 axis. In addition, 4-methylesculetin has the potential to be a therapeutic agent for T2DM.

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