Dendrobine inhibits hepatic gluconeogenesis and promotes glycogen synthesis through control of m6A RNA modification of PEPCK/G6Pase by METTL3 in hepatocytes

Disruption of glucose homeostasis in type 2 diabetes mellitus is characterized by increased glucose production and decreased glycogen content. Hepatic glucose metabolism is crucial in this disruption, with key enzymes like phosphoenolpyruvate carboxykinasen (PEPCK) and glucose-6-phosphatase (G6Pase) involved in gluconeogenesis and glycogen breakdown. m6A RNA modification, mediated by methyltransferase-like 3 (METTL3), regulates the expression of these enzymes and plays a significant role in glucose metabolism. Dendrobine, a natural sesquiterpene alkaloid, has various biological functions, but its impact on these processes remains unclear. This study aims to investigate the protective effects and mechanisms of dendrobine on hepatic glucose metabolism, particularly focusing on its modulation of PEPCK and G6Pase through m6A modification and METTL3 activity. The present findings reveal that dendrobine suppresses gluconeogenesis, promotes glycogen production, and modulates m6A modification levels of PEPCK and G6Pase RNAs in insulin-resistant hepatocytes. Additionally, dendrobine inhibits the glucosamine-induced upregulation of METTL3. Notably, the beneficial effects of dendrobine are partially reversed by METTL3 downregulation and changes in m6A modification levels of PEPCK and G6Pase RNAs. These results suggest that dendrobine mitigates aberrant glucose metabolism by modulating m6A modifications and METTL3 activity, highlighting its potential as a therapeutic candidate for insulin resistance in diabetes.