Multi-pathway-driven hepatic protection: Semaglutide combined with HIIT counteracts diabetic liver injury in db/db mice.

OBJECTIVE: Investigate the impact and mechanism of semaglutide (Sema) combined with high-intensity interval training (HIIT) on hepatic glucose/lipid metabolism in db/db mice using untargeted metabolomics. METHODS: Db/db mice were divided into model control, Sema alone, and Sema + HIIT groups, with db/m mice as controls. Sema (0.1 mg/kg/week) was administered subcutaneously, and the control group was subcutaneously injected with the same volume of distilled water. Engaging in HIIT swimming occurred for five consecutive days weekly. Weekly fasting plasma glucose (FPG), body mass, and food intake were assessed. After 8 weeks, blood/liver tissues were analyzed; liver metabolomics used LC-MS. RESULTS: Following an 8-week intervention, it was determined that the weight loss efficacy of Sema alone was suboptimal. The lowering of FPG did not differ significantly between the Sema alone and the combined intervention groups. The combined treatment demonstrated superior efficacy compared with Sema alone in enhancing liver weight, liver index, food intake, TG, TC, hepatic TG, and liver injury biomarkers (AST, ALT; P < 0.05). Histological findings indicated that the combination intervention markedly decreased fat vacuoles and inflammatory infiltration in hepatocytes (P < 0.001). A total of 721 differential metabolites were identified after the combined intervention, with primary alterations in amino acids and their derivatives, lipids, energy metabolism, and bile acids, encompassing key pathways such as the TCA cycle, amino acid metabolism, and bile acid metabolism. CONCLUSIONS: Semaglutide combined with HIIT synergistically improves hepatic glucose and lipid metabolism in diabetic mice, providing a new treatment strategy for liver lipid disorders.