Dihydromyricetin mitigates T2DM progression by modulating bile acid metabolism through SHP/PPARγ pathway

Dihydromyricetin (DHM) exhibits promising therapeutic effects in metabolic disorders, including type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear. This study aims to characterize the metabolites, genes, and proteins influenced by DHM under chronic hyperglycemia, thereby clarifying how DHM mitigates hyperglycemia and slows T2DM progression. Hyperglycemic rodent models were established by high-fat diet feeding, and DHM was administered orally to evaluate its hypoglycaemic and hypolipidemic effects. Transcriptomic profiling of liver tissues was performed to identify DHM-responsive genes, while bile acid composition in serum and liver were analyzed by LC-MS/MS. Functional studies in hepatocytes and mice were conducted to assess the metabolic roles of bile acids. Mechanistic insights were further obtained through gene editing, surface plasmon resonance (SPR), co-immunoprecipitation, and chromatin immunoprecipitation assays. DHM administration normalized total bile acid levels and impacted the expression of bile acid metabolism-related genes in hyperglycemic rodents. Secondary bile acids derived from the gut microbiota, such as lithocholic acid (LCA), were markedly elevated under hyperglycemia and impaired hepatic insulin signaling. Disruption of the small heterodimer partner (SHP) alleviated these adverse effects, including its role in mediating bile acid-induced insulin resistance. DHM restored insulin sensitivity and metabolic balance by modulating the SHP/peroxisome proliferator-activated receptor gamma (PPAR γ) pathway and counteracting the harmful effects of elevated secondary bile acids. By modulating gut microbiota-derived bile acid metabolism via the SHP/PPAR γ pathway, DHM improves insulin sensitivity and delays T2DM progression. This study reveals a novel mechanism underlying DHM action and supports its further development as a therapeutic strategy.