Synergistic Protective Effects of Ginsenoside Rb1 and Berberine Against Type 2 Diabetes Mellitus via the GDF15/HAMP Signaling Pathway Throughout the Liver Lobules: Insights from Spatial Transcriptomics Analysis

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a significant public health issue with high mortality and morbidity. Ginsenoside Rb1 and berberine, the main bioactive compounds of Panax ginseng and Coptis chinensis, respectively, are known for their hypoglycemic effects. Nevertheless, the synergistic effects and underlying mechanism of ginsenoside Rb1 and berberine on T2DM remain unclear. In this study, we utilized a leptin receptor- deficient (db/db) mouse model to investigate the protective effects of their combination treatment. Our findings demonstrated that the combined use of ginsenoside Rb1 and berberine at a 1:4 ratio had more pronounced effects than the first-line anti-diabetic drug metformin on reducing the weight ratio of white adipose tissue, ameliorating insulin resistance, and improving glucose and lipid metabolism. Using spatial transcriptomics, we revealed that metformin treatment improved gluconeogenesis and lipogenesis only in the periportal zone, while the combination treatment induced improvements throughout the liver lobule, with distinct key targets across different zones, thus underscoring a more comprehensive and nuanced modulation of hepatic metabolism. This may be the key reason why this combination therapy demonstrated superior protective effects against T2DM. Additionally, the reversed expression of the key callback gene Hamp and its regulator Gdf15 following the combination therapy across all zones, along with validation experiments, further suggested that the GDF15/HAMP signaling pathway might be a key mechanism underlying the beneficial effects of ginsenoside Rb1 and berberine against T2DM. This study also indicates a path toward innovative drug cocktails for treating T2DM, offering a holistic approach to regulate the entire liver lobule metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE285791 | GEO | 2025/12/26

REPOSITORIES: GEO