Qiyu Granules ameliorate insulin resistance via modulating PI3K/AKT/FoxO1 pathway and AMPK/PPAR γ pathway in diabetic KKAy mice

To investigate the protective effect and mechanism of Qiyu Granules in alleviating insulin resistance in KKAy mice. The chemical ingredients of Qiyu Granules were analyzed using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Network pharmacology and animal experiments were used to verify the pharmacological effects of Qiyu Granules in alleviating insulin resistance in diabetic KKAy mice and to explore its mechanism of action. High-sugar, high-fat chow was fed to KKAy mice for modeling. After 12 weeks, indicators of glucose metabolism (FBG, AUC), lipid metabolism (TC, TG, LDL, HDL, FFA), liver function (ALT, AST) and insulin resistance (FINS, HOMA-IR, HOMA- β, ISI) were detected. Pathological changes in pancreatic and liver tissues were observed by hematoxylin-eosin (H&E) and Oil Red O staining. Hepatic glycogen levels were analyzed using enzyme-linked immunosorbent assay (ELISA) method and periodic acid-Schiff (PAS) staining. Western blot was used to detect the protein expression levels of InsR, p-PI3 K, p-AKT, FoxO1, PEPCK, G6pase, p-AMPK, p-GSK-3β, GLUT2, PPAR γ and PPAR α. FBG, AUC, HOMA-IR, TC, TG, LDL, FFA, ALT, AST and hepatic index were decreased in mice treated with Qiyu Granules; while FINS, HOMA- β, ISI, HDL and hepatic glycogen content were increased. Qiyu Granules also improved histopathological changes in the pancreas and liver of KKAy mice. Besides, Qiyu Granules up-regulated the expression levels of InsR, p-PI3 K, p-AKT, p-AMPK, GLUT2 and PPAR α proteins in the livers of mice in the model group. However, Qiyu Granules down-regulated the expression levels of FoxO1, PEPCK, G6Pase, p-GSK-3 β and PPAR γ proteins. Qiyu Granules may regulate the InsR/PI3K/AKT/FoxO1 pathway, AMPK pathway, and PPAR γ /PPAR α pathway to ameliorate insulin resistance. Therefore, Qiyu Granules is a promising hypoglycaemic agent for the treatment of DM.