Exploring the synergistic and complementary effects of berberine and paeoniflorin in the treatment of type 2 diabetes mellitus by network pharmacology

Investigation of the synergistic and complementary effects is vital but difficult for Chinese herbal medicine. We explored the synergistic and complementary mechanisms of berberine (BBR) and paeoniflorin (PF) in the treatment of type 2 diabetes mellitus (T2DM) through network pharmacology and molecular docking. We identified putative targets of BBR, PF, and T2DM, and constructed a protein-protein interaction (PPI) network. Gene ontology and Kyoto encyclopedia of gene and genomes pathway enrichment analysis and molecular docking were used to predict the molecular mechanisms. A diabetes model was induced by a high-fat diet to verify the therapeutic effect. Ninety-two targets of BBR + PF in the treatment of T2DM were identified, which were considered as synergistic targets. Fifty-nine complementary targets of BBR-T2DM and 47 of PF-T2DM were identified. PPI network analysis showed that JAK2, ESR1, IFG1R, STAT3, EGFR, MAPK1, and AKT1 are closely related to T2DM. The enrichment analysis further showed that the synergistic targets mainly involved the AGE-RAGE signaling pathway in diabetic complications, FOXO, AMPK, and VEGF signaling pathways, and glycolysis/gluconeogenesis. AKT1, JAK2, and STAT3, which are common targets of the AGE-RAGE signaling pathway in diabetic complications and the FOXO signaling pathway, were chosen for docking with BBR and PF, respectively, and showed good binding activities. BBR + PF significantly reduced weight and fasting blood glucose, and alleviated insulin resistance. Moreover, BBR + PF promoted the phosphorylation of AKT1, JAK2, and STAT3. This study provides information to understand the synergistic and complementary mechanism of BBR + PF against T2DM, and may facilitate the development of new anti-T2DM drugs.