The transcriptomic-based disease network reveals synergistic therapeutic effect of total alkaloids from Coptis chinensis and total ginsenosides on type 2 diabetes mellitus

Coptis chinensis Franch. and Panax ginseng C. A. Mey. are valuable herbal medicines with thousands of years of history and extensive health benefits, including anti-diabetic effects. However, the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides on type 2 diabetes mellitus (T2DM) and its underlying mechanism are still unclear. Our findings indicated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides was 4:1, which had the best effect on improving insulin resistance and gluconeogenesis in primary mouse hepatocytes. The combination of the two in a 4:1 ratio had a significant synergistic effect on improving glucose tolerance, reducing fasting blood glucose (FBG), the weight ratio of epididymal white adipose tissue (eWAT), and the homeostasis model assessment of insulin resistance (HOMA-IR) in leptin receptor-deficient (db/db) mice. Subsequently, T2DM liver specific network was constructed based on our RNA sequencing experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions. The network recovery index (NRI) score of the combined treatment group with a 4:1 ratio was the highest, which was superior to the groups treated with total alkaloids from Coptis chinensis and total ginsenosides alone. Finally, we found that the activated adenosine 5’-monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling in the liver played an important role in the synergistic treatment of T2DM, which was verified by western blot experiment in db/db mice. In conclusion, our results indicated that the combination of total alkaloids from Coptis chinensis and total ginsenosides at a ratio of 4:1 can significantly improve insulin resistance, glucose and lipid metabolism disorders in db/db mice, and the effect was significantly better than that of taking them alone. The synergistic mechanism was related to the enhancement of AMPK/ACC signaling pathway.