Microbial Fermentation-Derived Dihydroquercetin Derivatives Exhibit Superior Efficacy in Ameliorating Insulin Resistance via JNK/PI3K/AKT Pathway Regulation Compared to Dihydroquercetin

Insulin resistance (IR) is a complex metabolic disorder characterized by diminished insulin sensitivity, leading to impaired glucose uptake and a potential progression to hyperglycemia and diabetes. While lifestyle modifications are essential, the limitations of current pharmacological interventions highlight the need for natural products with therapeutic benefits. This study introduces two novel dihydroquercetin (DHQ) derivatives, 8-hydroxy-dihydroquercetin (H-DHQ) and dihydroquercetin-7-<i>O</i>-β-d-(4″-<i>O</i>-methyl)-glucoside (DHQ-MG), developed through microbial fermentation using <i>Beauveria bassiana</i>. Results indicated that H-DHQ and DHQ-MG significantly enhanced the alleviation of IR in a HepG2 cell model compared with DHQ, with no significant differences noticed between DHQ-MG and H-DHQ. Mechanistic analyses revealed that these derivatives effectively reduced inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, thereby activating the JNK/PI3K/AKT signaling pathway to promote glycogen synthesis, suppress gluconeogenesis, and stimulate glucose transport. This research highlights the potential of H-DHQ and DHQ-MG as effective natural alternatives for managing IR, while also providing indirect evidence for the application of microbial fermentation as a strategy to modify natural flavonoids for this purpose.