Sinapine Modulates Glycogen and Lipid Synthesis via IRS1 – PI3K – AKT – GSK3β – GS Pathway in Insulin‐Resistant Models

This study investigates the effects of sinapine on glycogen synthesis and lipid metabolism in insulin-resistant HepG2 cell models and type 2 diabetes mellitus (T2DM) mice. Network pharmacology analysis integrated 288 potential sinapine targets and 920 insulin resistance-related targets, yielding 72 overlapping genes. KEGG enrichment of these genes identified one significantly enriched insulin resistance pathway, with target mapping concentrated on the IRS1-PI3K-AKT-GSK3β-GS axis, suggesting a key role in promoting hepatic glycogen synthesis. Molecular docking identified these key targets on this signaling pathway, with sinapine showing strong binding affinity to its nuclear proteins (below -4.0 kcal/mol). In vitro, sinapine treatment improved glucose uptake and glycogen synthesis, while reducing lipogenesis, lipid accumulation, and reactive oxygen species (ROS) levels. RT-qPCR and Western blot analyses confirmed that sinapine increases glycogen synthase activity. In T2DM mice, sinapine improved glucose and lipid metabolism, enhanced insulin sensitivity, and reduced blood glucose levels. Additionally, sinapine attenuated weight loss, improved liver index and histology, and regulated serum lipid profiles. Overall, this study reveals the molecular mechanism of sinapine in mitigating insulin resistance via modulation of the IRS1-PI3K-AKT-GSK3β-GS pathway, offering theoretical support for its potential application as a nutritional intervention to improve carbohydrate and lipid metabolism.