Baicalin restores metformin responsiveness by inhibiting ceramide biosynthesis via SPT and pPP2A/pAMPK axis
Abstract
Background: : and Purpose: The rising prevalence of metformin non-response in type 2 diabetes mellitus (T2DM) presents a major therapeutic hurdle. While baicalin combined with metformin exerts a synergistic hypoglycemic effect, the underlying mechanism of this combination therapy remains unclear. We identified the key regulatory metabolite of the baicalin-metformin combination via metabolomics, and clarified the molecular mechanism by which this metabolite mediates its synergistic hypoglycemic effect. Experimental Approach: We recruited metformin non-responder (NR) T2DM patients, and a humanized mouse model was established via fecal microbiota transplantation (FMT) to mimic clinical NR phenotype. This model was used to evaluate the hypoglycemic effect of baicalin combined with metformin. Through untargeted metabolomics and targeted lipidomics analyses, ceramide was identified as the key regulatory metabolite. In vitro, baicalin-treated HepG2 cells assessed its effect on serine palmitoyltransferase (SPT), ceramide synthesis rate-limiting enzyme . In vivo SPT inhibitor myriocin treatment validated ceramide’s role in regulating metformin responsiveness. Ultimately, we clarified the underlying molecular mechanism by which ceramide modulates the hypoglycemic effect of metformin via western blotting assays. Key Results : Baicalin restored metformin’s hypoglycemic effect in NR mice, correlating with decreased ceramide levels. Baicalin reduced ceramide production by inhibiting SPT,…
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