Xiasangju alleviates hepatic insulin resistance in db/db mice via AMPK pathway: Mechanisms and active components study.

Type 2 diabetes mellitus (T2DM), one of the prevalent chronic diseases, significantly impacts individuals and society. Xiasangju (XSJ), a herbal tea formulation, has been commonly used in traditional Chinese medicine. Accumulating evidence suggests that XSJ can alleviate metabolic syndrome by regulating glucose and lipid metabolism, lowering liver index and improving glucose tolerance. In the present study, db/db mice were used to examine the effect of XSJ on treating T2DM, and Western blotting was performed to explore the underlying anti-T2DM pharmacological mechanisms. With AMP-activated protein kinase (AMPK) chosen as the target protein, surface plasmon resonance (SPR)-LC-MS technology was used to identify potential active ingredients of XSJ. To further explore the role of potential active ingredients of XSJ, their effects were investigated in insulin resistance (IR)-HepG2 cells. Our results demonstrate that in diabetic db/db mice, XSJ activated the AMPK pathway, which regulated hepatic glucose metabolism and inhibited oxidative stress caused by hepatic NADPH oxidase 4 (NOX4), thereby ameliorating hepatic IR. By means of SPR-LC-MS experiments, 4-Methylesculetin was identified as an important active ingredient in XSJ. Subsequently, to further elucidate the effects of this ingredient, in IR-HepG2 cells, 4-Methylesculetin was found to mitigate oxidative stress, enhance glucose consumption, and promote glycogen synthesis. This study demonstrated that XSJ improved T2DM and mitigated oxidative stress by activating the AMPK pathway. Specifically, 4-Methylesculetin emerged as a promising therapeutic agent for T2DM.