Renshenjian decoction alleviates diabetes via HIF-1α/SPTLC2 pathway by targeting ceramide synthesis

Renshenjian decoction (RSJ) is a traditional recipe for treating diabetes in an ancient Chinese medical book, composed of Puerariae lobatae Radix and Ginseng Radix. Despite its traditional use, the mechanism of RSJ in improving diabetes has not been elucidated.

This research aimed to investigate the effects and underlying mechanisms of RSJ in treating diabetes.

Diabetic (T2DM) mice were induced using a high-fat diet coupled with streptozotocin injections. The effect of RSJ was assessed through biochemical and histopathological analyses of blood and liver samples to evaluate liver function and tissue damage in T2DM mice. The mechanism of RSJ in treating diabetes was explored using molecular docking, metabolomics, and molecular biology techniques. Additionally, the role of RSJ was further validated in T2DM mice treated with the HIF-1α stabilizer DMOG.

RSJ could enhance insulin sensitivity and lower blood glucose and lipids in T2DM mice. These effects may be related to various components in RSJ, including puerarin, ginsenoside Rb1, and ginsenoside Re. Liver metabonomics revealed 57 differential metabolites in the model and RSJ groups, with 22 enriched pathways, predominantly related to sphingolipid metabolism. Furthermore, qPCR and Western blot results demonstrated that RSJ dramatically decreases the expression of HIF-1α and SPTLC2, as well as the ceramide content in the liver of diabetic mice. These results were partially reversed by the DMOG.

RSJ can inhibit the expression of ceramide through the HIF-1α/SPTLC2 pathway, which helps to improve diabetes and diabetes-related dyslipidemia and liver injury.