Tangzhiwan pills (TG) ameliorate type 2 diabetes by restoring hepatic glycolysis/gluconeogenesis via the PPAR signaling pathway.

BACKGROUND

Type 2 diabetes mellitus (T2DM) is a global health challenge associated with significant morbidity and mortality. Previous studies have indicated that the traditional Chinese medicine formula Tangzhiwan pills (TG) exhibits therapeutic potential against T2DM. However, the precise molecular mechanisms underlying its therapeutic efficacy, particularly at the systemic multiomics level, remain largely unexplored.

METHODS

The main components of TG pills were analyzed by LC‒MS. RNA-seq and metabolomics were used to analyze the potential mechanism. A rat model of T2DM was established, and integrated metabolomics and transcriptomics analyses were conducted on liver tissue before and after TG treatment. Network pharmacology was deployed to identify bioactive metabolites and underlying targets of TG for improving T2DM.

RESULTS

TG treatment effectively ameliorated key pathological features of T2DM, including hyperglycemia, impaired glucose tolerance, dyslipidemia, and hepatic inflammatory cell infiltration. Integrated multiomics analyses identified dysregulated hepatic glycolysis/gluconeogenesis as a central metabolic perturbation in T2DM, which was effectively normalized by TG treatment. This restoration was mechanistically linked to the concurrent modulation of the PPAR and p53 signaling pathways. These interactions target the p53 and PPAR signaling pathways, thereby inhibiting the expression of associated genes.

CONCLUSION

Collectively, our study delineates a novel multitarget mechanism whereby TG, via its bioactive components (e.g., 6-demethoxytangeretin and naringin), concurrently modulates the PPAR and p53 signaling axes to restore hepatic glucose metabolic homeostasis, offering a mechanistic rationale for its clinical application in T2DM management.