The transcriptomic-based disease network reveals synergistic therapeutic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng 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 from Panax ginseng 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 from Panax ginseng 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 from Panax ginseng 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 from Panax ginseng 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.