Abstract: This study aims to investigate the ameliorative effects and mechanisms of Poria cocos polysaccharide (PCP) on glucose and lipid metabolism, as well as oxidative stress, in a diabetic model of C57BL/6J mice. Type 2 diabetes mellitus (T2DM) was induced in the mice through a combination of a high-fat diet and streptozotocin (STZ) injection. The mice were then randomly divided into five groups: normal control, diabetic control, low-dose PCP group (50 mg/kg), high-dose PCP group (100 mg/kg), and rosiglitazone group(RSG). After receiving the corresponding treatments and being gavaged continuously for six weeks, the blood glucose, insulin, hepatic glycogen, muscular glycogen, blood lipids, and oxidative stress indicators were measured. Western blot analysis was conducted to assess the protein levels of glucose transporter 2 (GLUT2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT). To investigate the role of GLUT2 in the regulation of glucose and lipid metabolism, as well as oxidative stress by PCP, the mice were injected with adenoviral vectors encoding GLUT2 shRNA (Ad-GLUT2 shRNA) via their tail veins. The results demonstrated that PCP significantly enhanced glucose tolerance and insulin sensitivity in the mice,resulting in decreased levels of fasting blood glucose and insulin.Additionally,it increased hepatic and muscle glycogen levels,indicating its anti-hyperglycemic effect.Simultaneously,PCP significantly reduced body weight,liver tissue weight,epididymal fat weight,and subcutaneous fat weight in the mice.Furthermore,it improved lipid profiles by lowering total cholesterol (TC),triglycerides (TG),low-density lipoprotein cholesterol (LDL-C),and free fatty acid (FFA) levels,while elevating high-density lipoprotein cholesterol (HDL-C) levels.Furthermore,PCP alleviated oxidative stress by enhancing antioxidant enzyme activities,such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px),and reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA).Mechanistic studies revealed that PCP promoted glucose uptake and utilization by activating the glucose transporter 2 (GLUT2)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway,thereby regulating glucose and lipid metabolism.Furthermore,PCP augmented the expression of antioxidant genes,including NRF2,HO-1,and NQO-1,thereby further ameliorating oxidative stress conditions.GLUT2 knockdown experiments further substantiated that PCP′s beneficial effects on glucose and lipid metabolism,as well as oxidative stress,which were mediated through the modulation of GLUT2 expression.In summary,Poria cocos polysaccharide demonstrates notable anti-hyperglycemic,hypolipidemic,and antioxidant properties in diabetic models,furnishing a scientific rationale for the potential development of PCP as an adjunctive therapeutic agent in the management of diabetes.

Key words: Poria cocos polysaccharide, diabetes mellitus, glycolipid metabolism, oxidative stress disorder, GLUT2/PI3K/AKT signaling pathway