Abstract: To study the hypoglycemic effect and mechanisms of vaccine HSP65-6P277 protein on type 1 diabetic mice induced by streptozotocin(STZ), Lactococcus lactis live vector was used to express the vaccine protein. The mouse model of type 1 diabetes mellitus were established by intraperitoneal injections of multiple low dose STZ(MLD-STZ)and divided into three groups. The inducible expression strain L. lactis NZ9000 pCYT ∶HSP65-6P277, constitutive expression strain L. lactis NZ9000 pHJ ∶HSP65-6P277 and control strains L. lactis NZ9000 pCYT ∶Nuc were respectively immunized to diabetic mice orally once daily(2×10⁹ CFU, 200 μL)in the first week and once every week in the following weeks lasting for 16 weeks. Fasting blood glucose levels were measured once a month on blood samples taken from orbital venous plexus. Four months later, the mice were sacrificed. Spleen cell proliferation experiment was performed. IL-10 and IFN-γ cytokine levels of spleen cells and serum IgG levels were assayed using ELISA kits. The results showed that pCYT ∶HSP65-6P277 group and pHJ ∶HSP65-6P277 group have low blood glucose(P < 0. 05), and maintain normal body weight, compared with control group(pCYT ∶Nuc). On the other hand, cytokine IFN-γ levels were significantly lower(P < 0. 05)in spleen cells supernatant and spleen cell proliferation was reduced against HSP65 and P277(P< 0. 05), but serum IgG levels were not significantly different(P> 0. 05).