Hovenia dulcis (Guaizao) polysaccharide ameliorates hyperglycemia through multiple signaling pathways in rats with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) poses a significant threat to human health, with its incidence and mortality rates increasing annually. This study investigated the hypoglycemic effects and underlying mechanisms of pure Hovenia dulcis (Guaizao) polysaccharide (HDPs-2A) in rats subjected to a high-fat and high-sugar diet combined with streptozotocin-induced T2DM. Oral administration of HDPs-2A resulted in significant increases in body weight and liver glycogen levels compared to untreated controls. Moreover, a reduction in fasting blood glucose levels, alleviation of hyperinsulinemia, enhanced glucose tolerance, and improved insulin resistance were observed in the HDPs-2A-treated group. HDPs-2A also effectively reversed diabetes-induced dyslipidemia, as evidenced by decreased total cholesterol and triglyceride levels, alongside increased high-density lipoprotein cholesterol levels. Histopathological analyses confirmed that HDPs-2A partially repaired liver tissue damage by mitigating oxidative stress responses in the liver. Additionally, treatment with HDPs-2A significantly elevated short-chain fatty acid levels in T2DM rats. Real-time quantitative PCR and Western blot analyses indicated that HDPs-2A significantly enhanced the expression of InsR, IRS2, PI3K, Akt, and GLUT4, suggesting that HDPs-2A regulates insulin resistance and glycometabolism through the activation of the PI3K/Akt signaling pathway. Furthermore, HDPs-2A appeared to modulate the expression of GS, GSK-3(3, and FoxO1 to improve glucose metabolism and reduce insulin resistance. It also improved glucose metabolism by activating the AMPK pathway and modulating G6Pase and PEPCK expression. This study provides novel insights into the antidiabetic effects of HDPs, positioning them as promising nutritional agents for the management of T2DM.