Effects of Exercise Combined with Metformin on Blood Glucose and Skeletal Muscle AMPK Signal Pathway in T2DM Rats

WANG Baoming; CHANG Yixing; LIAN Zhenzhen; YI Xuejie

doi:10.3969/j.issn.2096-305X.2025.03.001

Abstract：Objective To investigate whether exercise combined with metformin regulates glucose homeostasis by repairing the AMPK signaling pathway in the skeletal muscle of T2DM rats and further clarify whether it has a synergistic effect.Methods 55 weaned Sprague-Dawley(SD)rats were randomly divided into five groups:normal control(NC),diabetic control(DC),diabetic exercise(DE),diabetic metformin(DM),and diabetic exercise combined with metformin(DEM).After successful modeling,the DE group underwent swimming training only,the DM group received metformin intervention(gavage,500 mg/kg),and the DEM group underwent both swimming training and metformin intervention.After six weeks of intervention,venous blood and gastrocnemius muscle samples were collected from each group to detect blood glucose levels,serum insulin concentrations,and the expression levels of key proteins in the skeletal muscle LKB1/AMPK/GLUT4 signaling pathway.Results After 6 weeks of intervention,compared with the NC group,the DC group showed significantly increased blood glucose and insulin levels(P<0.05).Compared with the DC group,the DEM group exhibited significantly reduced blood glucose levels,while the DE,DM,and DEM groups showed significantly decreased insulin levels(P<0.05).Additionally,glucose clearance rate GCR and muscle glycogen content in the DEM group were significantly increased(P<0.05).In skeletal muscle,compared with the NC group,the DC group showed significantly decreased levels of p-LKB1,AMPKα2,p-AMPKα2,and GLUT4(P<0.05).Compared with the DC group,the DE group had significantly increased AMPKα2 and GLUT4 levels(P<0.05);the DM group had significantly increased p-LKB1 and AMPKα2 levels(P<0.05);the DEM group showed significantly increased levels of p-LKB1,AMPKα2,p-AMPKα2,and GLUT4(P<0.05).Conclusion A six-week intervention with either exercise or metformin can improve hyperinsulinemia in T2DM rats;however,the hypoglycemic effect of a single intervention is not significant,possibly due to the limited intervention duration and sample size.After a combined intervention for 6 weeks,insulin sensitivity can be significantly improved and blood sugar levels can be reduced,potentially through p-LKB1-mediated AMPK activation and upregulation of GLUT4 expression.In the future,it is necessary to further explore the effect of intervention lasting for 10 weeks on the glycolytic metabolism of skeletal muscles,in order to optimize the prevention and treatment strategies for type 2 diabetes mellitus.