Molecular Mechanism Of CREBH-FGF21 Axis Mediated Exercise And Metformin Regulating Liver Glucose Metabolism In Db/db Mice

OBJECTIVE: To investigate the effects of exercise and metformin intervention on blood glucose,liver gluconeogenesis-related indexes and key enzyme activities and contents,and CREBH-FGF21 axis protein expression in db/db mice.Explore the mechanism of CREBH-FGF21 axis involved in exercise and metformin regulation of liver glucose metabolism in db/db mice.METHODS: 40 db/db mice were randomly divided into control quiet group(C),exercise only group(E),metformin only group(M),and exercise + metformin group(EM),7～10 mice in each group.Fasting blood glucose and quiet blood lactate levels of mice were measured weekly,and serum and liver tissues were taken at the end of 8weeks of intervention.Serum and liver tissue FGF21 levels,liver PEPCK and G6 pase activities and gene protein levels of PEPCK,G6 pase,CREBH and FGF21 were measured.RESULTS:(1)Exercise or metformin intervention alone significantly reduced body weight in db/db mice,and exercise combined with metformin intervention significantly reduced fasting glucose,improve insulin resistance while blood lactate level increased;(2)liver glycogen content increased and PEPCK expression decreased in group E,no significant changes in liver glycogen content,gluconeogenic enzyme activity and expression in group M,and liver glycogen content significantly decreased in group EM while PEPCK,G6 pase activity and expression G6 pase activity and expression decreased in the EM group.(3)There were no significant changes in CREBH content in the E and M groups,a significant increase in serum FGF21 level and liver FGF21 expression in the M group,and a significant downregulation of CREBH-FGF21 axis protein level in the EM group.CONCLUSION: exercise alone significantly promoted hepatic glycogen synthesis in db/db mice,with no significant change in hepatic gluconeogenesis and poor hypoglycemic effect.Metformin intervention alone did not significantly regulate gluconeogenesis,but showed increased hepatic FGF21 expression.In contrast,exercise combined with metformin could down-regulate CREBH-FGF21 axis,improve insulin resistance,significantly inhibit gluconeogenic enzyme activity and content,reduce liver gluconeogenesis level,and have significant glucose-lowering effect.