Abstract: OBJECTIVE To observe the effect of Tangzhiqing on the endoplasmic reticulum stress related factors GPR78， CHOP and Caspase-12 in hippocampus of diabetic rats， and to explore its mechanism of improving cognitive function in diabetic rats. METHODS The model of type 2 diabetes mellitus rats was established by intraperitoneal injection of low-dose of streptozotocin combined with high-sugar and high-fat diet， After 8 weeks of intervention with high， medium and low-dose of Tangzhiqing， serum fasting glucose (FPG) and fasting insulin (FINS) were detected by ELISA， the index of insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) were calculated; the expression levels of endoplasmic reticulum stress related genes GPR78， CHOP and Caspase-12 mRNA and protein in hippocampus were detected by qPCR and Western blot assay. RESULTS Different dosages of Tangzhiqing significantly decreased FPG and HOMA-IR ( P <0.01); except the low dose group， Tangzhiqing significantly improved ISI ( P <0.01); no significant difference existed in FPG level among the 3 groups ( P >0.05). Compared to the model group， the relative expression of GRP78 mRNA and protein in the 3 groups of Tangzhiqing increased significantly， and the expression of CHOP and Caspase-12 mRNA in these 3 groups decreased ( P <0.01). CHOP and Caspase-12 in middle and high dose group decreased significantly ( P <0.01). CONCLUSION Tangzhiqing can control blood sugar， improve insulin resistance， increase insulin sensitivity and regulate the expression of GRP78， CHOP， Caspase-12 in hippocampus.