Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction

Rationale: Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes.Ginsenosides are reported to have antidiabetic activities.Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng.This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production.Methods: The effects of Rg1 were investigated in high-fat-diet (HFD)-fed mice and glucagon-challenged C57BL/6J mice.Glucose metabolism was evaluated by oral glucose tolerance test and pyruvate tolerance test.The role of Rg1 on the regulation of Akt-FoxO1 interaction was performed using immunofluorescence, immunoprecipitation, siRNA silencing, pharmacological inhibitor and active-site mutant in primary hepatocytes or HepG2 cells.Results: Abnormally elevated fasting glucagon levels were observed in HFD-fed mice, contributing significantly to increased fasting plasma glucose levels.Inappropriate fasting glucagon secretion inactivated Akt and promoted hepatic glucose production via upregulation of FoxO1 activity.Rg1 preserved glucagon-impaired Akt activation partly by binding to Akt at Ser473 site.Rg1 also promoted Akt binding to FoxO1 and inactivated FoxO1 by phosphorylation.Consequently, Rg1 decreased the hepatic glucose production through a decrease in transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase).Both siRNA silencing of Akt and Akt inhibitor triciribine attenuated the effects of Rg1 in response to fasting hormone glucagon.Conclusion: Akt phosphorylation at Ser473 by ginsenoside Rg1 is critical for its gluconeogenesis-lowering effect, suggesting a potential for pharmaceutical intervention in response to fasting hormone glucagon.