Effect of Astragaloside Ⅳ in Regulating PI3K/Akt/FoxO1 Pathway and Inhibiting Hepatic Gluconeogenesis in Diabetic Rats / 中国实验方剂学杂志

ABSTRACT

<b>Objective:To investigate the potential mechanism of astragaloside Ⅳ in protecting liver injury and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/forkheadbox transcription factor 1 (FoxO1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) protein expressions in type 2 diabetic (T2DM) rats. <b>Method:After 6 weeks of high-sugar and high-fat diet, a model of type 2 diabetes was established through intraperitoneal injection of streptozotocin (STZ, 0.035 g·kg^-1). The rats were randomly divided into normal group, model group, low, medium and high-dose astragaloside Ⅳ groups and metformin group, 0.02, 0.04, 0.08 g·kg^-1·d^-1 astragaloside crude drug and 0.2 g·kg^-1·d^-1 metformin were administered in the low, middle and high-dose astragaloside Ⅳ and metformin groups. After 8 weeks of continuous administration, and 24 hours later after the last gavage, the rats were executed. Serum and liver tissues were collected to detect serum liver biochemical indexes, liver index HDL-C. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of liver tissue. Masson staining was used to observe the degree of liver fibrosis. The changes of glycogen, glycoprotein, or mucopolysaccharide in tissue cells were observed by periodic acid Schiff (PAS) reaction staining. Immunohistochemistry and Western blot analysis were used to detect the expression levels of PI3K/Akt/FoxO1 signaling protein and PEPCK and G6Pase in liver tissues of each group. <b>Result:Compared with normal group, the liver index of the model group increased significantly (<italic>P</italic><0.01), the levels of liver function indicators alanine aminotransferase(ALT), aspartate aminotransferase(AST), TC and TG were significantly increased (<italic>P</italic><0.01), while HDL-C and body weight were significantly reduced (<italic>P</italic><0.01). The results of immunohistochemistry and Western blot showed that the signal of PI3K/Akt/FoxO1 was weakened (<italic>P</italic><0.01), and PEPCK and G6Pase were increased (<italic>P</italic><0.01) in model group. Compared with model group, the contents of ALT, AST, TC and TG in middle and high-dose astragaloside Ⅳ groups were significantly decreased (<italic>P</italic><0.05, <italic>P</italic><0.01), while the body weight was significantly increased (<italic>P</italic><0.05, <italic>P</italic><0.01), the middle and high dose of astragaloside Ⅳ significantly inhibited the levels of FoxO1, PEPCK and G6Pase in liver tissue (<italic>P</italic><0.05, <italic>P</italic>< 0.01), and enhanced the phosphorylation of FoxO1 (<italic>P</italic><0.05, <italic>P</italic><0.01). <b>Conclusion:Astragaloside Ⅳ may inhibit T2DM hepatic gluconeogenesis by regulating PI3K/Akt/FoxO1 signaling pathway, and inhibiting high-fat, high-sugar and low-dose STZ, thereby protecting liver damage in T2DM rats.