LIAN Li-rong, SHU Xiao, HUANG Bao-li, XIE Wei, HE Jin-lian, LI Run-ze, ZHAO Heng-xia, LIU Liang
Objective： To investigate the effects and underlying mechanisms of Heqi San in improving insulin resistance in newly diagnosed type 2 diabetes mellitus (T2DM). Methods： Network pharmacology was employed to predict the key targets and signaling pathways involved in Heqi San's intervention in T2DM-related insulin resistance. A rat model of T2DM with insulin resistance was then established. Animals were divided into five groups: normal control, model, metformin, high-dose Heqi San, and low-dose Heqi San. The effects of Heqi San on blood glucose, insulin resistance, lipid levels, and hepatic histopathological changes were evaluated. Western blot and ELISA were used to detect the expression of key proteins and inflammatory cytokines in liver tissue and serum to verify the accuracy of the network pharmacology predictions. Results： Network pharmacology analysis predicted that Heqi San may act through multiple targets, particularly by modulating the AGEs/RAGE/PI3K/AKT signaling pathway. In vivo experiments demonstrated that high-dose Heqi San significantly reduced fasting blood glucose and HOMA-IR index, alleviated insulin resistance and dyslipidemia, and ameliorated hepatic steatosis. Mechanistically, Heqi San inhibited the expression of AGEs and RAGE, suppressed NF-κB activation, reduced inflammatory cytokines TNF-α and IL-6, relieved inhibition of the PI3K/AKT pathway, increased GLUT2 expression, and enhanced hepatic glucose metabolism. Conclusion： Heqi San improves insulin signaling by modulating the AGEs/RAGE/PI3K/AKT pathway, thereby alleviating hepatic insulin resistance, regulating lipid and glucose metabolism, and exerting hypoglycemic, lipid-lowering, and hepatoprotective effects. These findings provide experimental evidence supporting the use of Heqi San in the treatment of newly diagnosed T2DM insulin resistance.
