Integration of Pharmacodynamics, Proteomics, and Metabolomics to Elucidate Effect and Mechanism of Rehmanniae Radix in the Treatment of T2DM

ABSTRACT Rehmanniae Radix (RR) has a long history in treating type 2 diabetes mellitus (T2DM). It was previously shown to alleviate T2DM through the regulation of molecular targets in the kidney. However, the role of RR on T2DM‐driven hepatic metabolism disorder remains unclear. This study aimed to elucidate the therapeutic effects of RR against T2DM and reveal its mechanism of action in the liver. In this study, a high‐fat diet and streptozotocin‐induced T2DM rat model were used to investigate the antidiabetic effect of Rehmanniae Radix extract (RRE). Proteomics and metabolomics of rat serum and livers were employed to predict antidiabetic targets and metabolic pathways of RRE in the treatment of T2DM. After 5‐week oral administration, low, medium, and high doses of RRE all exhibited significant hypoglycemic effects, notably improving insulin resistance in T2DM rats. Additionally, 78 differentially expressed proteins returning to normal levels were identified in the serum, whereas 83 and 69 differentially expressed metabolites returning to normal levels were identified in the serum and liver, respectively. KEGG enrichment analysis from the proteomics and metabolomics data revealed enrichment of both ATP‐binding cassette (ABC) transporters and multiple lipid metabolism‐related pathways, which are highly associated with the antidiabetic effect of RRE. Pearson's correlation analysis showed significant correlations between differential proteins involved in cholesterol metabolism and differential metabolites related to lipid metabolism pathways in serum and liver. Furthermore, RT‐qPCR results demonstrated significant downregulation of mRNA levels of ATP‐binding cassette transporter A1 (Abca1) and ATP‐binding cassette subfamily G member 5 (Abcg5), upregulation of mRNA level of Glucose transporter type 1 (Glut1) and a decrease in hepatic glycogen content in the RRE‐treated T2DM rats. In conclusion, RRE exhibits a potent antidiabetic effect by downregulating Abca1 and Abcg5 to inhibit hepatic cholesterol efflux, promoting low‐density lipoprotein cholesterol clearance, upregulating Glut1 to increase hepatic glucose uptake, and lowering blood glucose levels, thereby improving glucose and lipid metabolism disorders.