Abstract: To investigate different irradiation doses of Se-enriched A.Auricularia polysaccharide (SAAP) in type 1 diabetes mellitus (T1DM) mice. In this study, extraction of polysaccharides from selenium-enriched fungus was carried out after ⁶⁰Co-γ-ray irradiation treatment. The optimal extraction conditions of SAAP were optimized by response surface methodology. The optimal irradiation dose was selected for the study of in vivo hypoglycemia by comparing the hypoglycemic effect of SAAP under different irradiation doses. C57BL/6 T1DM mice model was established by injecting streptozotocin (STZ) to evaluate the effects of fasting blood glucose (FBG), oral glucose tolerance (OGTT), and SAAP on the glucolipid metabolism and the regulation of oxidative stress in T1DM mice. The results showed that after response surface optimization, the optimal extraction conditions for SAAP: Material-liquid ratio of 37.98:1 mL/g, extraction temperature of 97.94 ℃, extraction time of 3.42 h. The optimal parameters were as follows: liquid-material ratio of 38:1 mL/g, extraction temperature 98 ℃, extraction time of 3.5 h, and SAAP concentration of 0.73 mg/mL. SAAP could improve the symptoms of polydipsia, polyphagia and weight loss in T1DM mice (P<0.05). SAAP was able to regulate blood glucose levels in T1DM mice, as evidenced by a decrease in FBG and OGTT. SAAP was able to significantly reduce total cholesterol (TC), triglyceride (TG) content, and malondialdehyde (MDA) content (P<0.05), as well as increased the levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) in T1DM mice. SAAP was able to attenuate the inflammatory response to T1DM, the levels of interferon β (IFN-β), interleukin 18 (IL-18), interleukin 6 receptor (IL-6R), and tumor necrosis factor (TNF-γ) were reduced in direct proportion to the irradiation. The protective effect of SAAP on T1DM mice was achieved by inhibiting the PI3K/AKT/mTOR signaling pathway, and the inhibitory effect was best at an irradiation dose of 10 kGy. This study provides a theoretical basis and technical reference for the application of SAAP in the treatment of T1DM-induced inflammation and oxidative stress.