Abstract: This study aims to investigate the hypoglycemic effects and underlying mechanisms of metabolites of Irpex lacteus (MIL) on type 2 diabetic mice. T2DM mice model was induced by intraperitoneal injection of streptozotocin (STZ), and the mice were divided into normal group, model group, metformin group, and MIL high, medium, and low dose groups. After 5 weeks of administration, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), liver glycogen, serum creatinine (SCR), blood urea nitrogen (BUN), insulin (INS), and glucose transporter 4 (GLUT4) levels were measured, and pathological observations of the kidneys were conducted. Network pharmacology was used to predict pathways and targets. RT-qPCR and Western blot were employed to detect the mRNA and protein expression levels of related genes of T2DM mice. The results indicate that MIL can significantly reduce the levels of FBG, BUN, SCR, INS, and OGTT-AUC in T2DM mice (P<0.01), and significantly increase the levels of GLUT4 and Liver Glycogen (P<0.01). Renal pathological observations show that MIL can improve the inflammatory state of cells in renal tissue and effectively alleviate nephritis symptoms caused by hyperglycemia. Additionally, MIL significantly upregulated the mRNA expression levels of protein kinase B (AKT), GLUT4, and phosphatidylinositol 3-kinase (PI3K), while downregulating INS expression, notably increased the protein expression levels of p-PI3K and p-AKT. These findings suggest that MIL may regulate blood glucose disorders by activating the PI3K/AKT signaling pathway.