Licochalcone D from Glycyrrhiza uralensis Improves High-Glucose-Induced Insulin Resistance in Hepatocytes

This study investigated the therapeutic potential of licochalcone D (LicoD), which is derived from Glycyrrhiza uralensis, for improving glucose metabolism in AML12 hepatocytes with high-glucose-induced insulin resistance (IR). Ultra-high-performance liquid chromatography–mass spectrometry revealed that the LicoD content of G. uralensis was 8.61 µg/100 mg in the ethanol extract (GUE) and 0.85 µg/100 mg in the hot water extract. GUE and LicoD enhanced glucose consumption and uptake, as well as Glut2 mRNA expression, in high-glucose-induced IR AML12 cells. These effects were associated with the activation of the insulin receptor substrate/phosphatidylinositol-3 kinase signaling pathway, increased protein kinase B α phosphorylation, and suppression of gluconeogenesis-related genes, such as Pepck and G6pase. Furthermore, GUE and LicoD promoted glycogen synthesis by downregulating glycogen phosphorylase. Furthermore, LicoD and GUE mitigated the downregulated expression of mitochondrial oxidative phosphorylation proteins in IR hepatocytes by activating the PPARα/PGC1α pathway and increasing the mitochondrial DNA content. These findings demonstrate the potential of LicoD and GUE as therapeutic options for alleviating IR-induced metabolic disorders by improving glucose metabolism and mitochondrial function.