1H NMR-Based Metabolomics Coupled With Molecular Docking Reveal the Anti-Diabetic Effects and Potential Active Components ofBerberis vernaeon Type 2 Diabetic Rats

The dried stem bark ofBerberis vernaeC.K.Schneid., known as "Xiao-bo-pi" in Chinese, is a representative anti-diabetic herb in traditional Tibetan medical system. However, its anti-diabetic mechanisms and active components remain unclear. In this study,H-1 NMR-based metabolomics, biochemistry assay, molecular docking, and network analysis were integrated to evaluate the anti-diabetic effects ofB. vernaeextract on type 2 diabetic rats, and to explore its active components and underlying mechanisms. Diabetes was induced by high-fat diet and streptozotocin. After 30 days of treatment,B. vernaeextract significantly decreased the serum levels of fasting blood glucose, insulin, insulin resistance index, glycated serum protein, TNF-alpha, IL-1 beta, and IL-6, whereas significantly increased the serum levels of insulin sensitivity index in type 2 diabetic rats. A total of 28 endogenous metabolites were identified by(1)H NMR-based metabolomics, of which 9 metabolites that were changed by diabetes were significantly reversed byB. vernaeextract. The constructed compound-protein-metabolite-disease (CPMD) interaction network revealed the correlation between chemical constituents, target proteins, differential metabolites, and type 2 diabetes. Ferulic acid 4-O-beta-D-glucopyranoside, bufotenidine, jatrorrhizine, and berberine showed good hit rates for both the 30 disease-related proteins and 14 differential metabolites-related proteins, indicating that these four compounds might be the active ingredients ofB. vernaeagainst type 2 diabetes. Moreover, pathway analysis revealed that the anti-diabetic mechanisms ofB. vernaemight be related to its regulation of several metabolic pathways (e.g., butanoate metabolism) and disease-related signal pathways (e.g., adipocytokine signaling pathway). In summary,B. vernaeexerts a significant anti-diabetic effect and has potential as a drug candidate for the treatment of type 2 diabetes.