Objective To study the changes in expression of peroxisome proliferatoractivated receptor-γ co-activator-1α (PGC-1α) and sirtuin (silent mating type information regulation 2 homolog)1 (S. cerevisiae)(SIRT1) in the hippocampal tissues of type 2 diabetes mellitus rats and to discuss its significance. Methods Diabetic models were induced by highfat diet and intraperitoneal injection of streptozotocin (STZ) in SD rats. Then the rats were divided into model group and αlipoic acid group randomly. Healthy rats served as controls. All of the rats were tested by Morris water maze after 8 weeks, and then the hippocampus tissues of animals were prepared for TUNEL assay and transmission electron microscopy (TEM) observation. The expression of PGC-1α mRNA was examined by RTPCR, and the expression of PGC-1 α and SIRT1 protein were examined by Western blotting analysis. Moreover, the activities of superoxide dismutase (SOD), glutathione (GSH), and the content of malondialdehyde (MDA) were all examined using corresponding kits. Results Compared with the control group, 8 weeks later the model group had significantly decreased cognitive function (P<0.05), with evident apoptotic neurons and prominent ultrastructure damage in the hippocampus tissues. Moreover, the model group had significantly lower SOD and GSH activities, PGC-1 α mRNA and protein expression, and SIRT1 protein expression (P<0.01), and significantly higher MDA content (P<0.01). When compared with the model group, rats in the α-lipoic acid group showed significantly improved cognitive function (P<0.05) and lower levels of neuron apoptosis and ultrastructure damage; and the expressions of PGC1α mRNA and protein, SIRT1 protein and the activities of SOD and GSH were significantly increased in the αlipoic acid group (P<0.01), while the content of MDA was significantly declined (P<0.05).Conclusion High glucose condition inhibits the expression of SIRT1, resulting in the dysfunction of PGC-1α, which might be an important factor for diabetes cognitive impairment.