2445-P: Baicalein Alleviates Skeletal Muscle Insulin Resistance in T2DM by Modulating the AEBP1/p110β Pathway

Introduction and Objective: The pathogenesis of type 2 diabetes mellitus (T2DM) is closely associated with skeletal muscle insulin resistance (IR). baicalein, the primary component of Scutellaria baicalensis Georgi, exhibits hypoglycaemic and lipid-regulating effects while improving skeletal muscle IR. Our prior research revealed that AEBP1 induces skeletal muscle IR by interacting with p110β. This study aims to investigate whether baicalein mitigates skeletal muscle IR in T2DM via the AEBP1/p110β pathway. Methods: The efficacy of baicalein and its effects on AEBP1/p110β expression were investigated using T2DM mouse and cellular IR models. In C2C12 and HSkMC cells, the regulatory role of baicalein on AEBP1/p110β was explored via AEBP1 overexpression and knockdown (AEBP1-OE/KD). Molecular docking, co-IP, CETSA, SPR, molecular dynamics simulations, and site-directed mutagenesis were employed to elucidate the intermolecular interaction mechanisms. Results: Baicalein improves glucose tolerance and insulin sensitivity in mice, alleviates IR in skeletal muscle tissues and cells, enhances skeletal muscle function, and modulates the protein expression levels of AEBP1 and p110β in tissues and cells. However, in both skeletal muscle cell types, AEBP1-OE/KD significantly affected p110β expression and the aforementioned effects of baicalein. Protein interactions revealed that baicalein inhibits the interaction between AEBP1 and p110β, attributed to its binding at the K870 site of AEBP1. Conclusion: Baicalein alleviates skeletal muscle IR in T2DM by binding to the K870 site of AEBP1 and modulating the AEBP1/p110β pathway. Disclosure C. Guo: None. H. Wang: None. C. Tang: None. Funding the National Natural Science Foundation of China (82405357)