BACKGROUND: Some studies have shown that down-regulation of Wnt/β-catenin signaling is closely related to the pathogenesis of cognitive impairments and exercise can delay the pathological process of diabetes, but its molecular mechanism needs further investigation. OBJECTIVE: To investigate the effect and molecular mechanism of 8-week treadmill training on cognitive impairment in diabetic rats. METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into a control group (n=10) and a diabetes model group (n=20) according to the random number table. After the model was successfully established, 10 model rats were randomly selected as the diabetes exercise group. After 8 weeks of exercise intervention, the expressions of neurotrophic factors, cell cycle, apoptosis, aging and Wnt signaling pathway-related proteins in the rat hippocampus of each group were detected by Morris water maze, Nissl and NeuN staining, and western blot assay. RESULTS AND CONCLUSION: The results of Morris water maze showed that compared with the control group, the escape latency of rats was longer, the number of platform crossing was significantly reduced, and the swimming trajectory was more complex in the diabetes model group (P < 0.05). After 8 weeks of treadmill intervention, the escape latency was significantly shortened and the behavioral trajectory was simpler. The Nissl staining results showed that compared with the control group, the Nissl bodies in the hippocampus of diabetic rats were smaller and the number was decreased, with the cell body shrinking, nucleus shrinking and loose arrangement. However, compared with the diabetes model group, the hippocampal Nissl bodies in the diabetes exercise group were increased in size and number, and the morphological structure tended to be normal. Western blot results showed that the expression levels of cAMP response element binding protein and brain-derived neurotrophic factor protein in the diabetes model group were significantly decreased compared with those in the control group (P < 0.001, P < 0.05), while the 8-week treadmill exercise increased their expressions. Meanwhile, compared with the control group, the expression levels of CDK5, cyclin D1 and Caspase-3 were significantly increased in the diabetes model group (P < 0.001, P < 0.05), while the 8-week treadmill exercise reduced the expression of cell cycle and apoptosis-related proteins. In addition, compared with the control group, the expression of Sirt1 protein was significantly down-regulated in the diabetes model group (P < 0.001), and the expressions of p53 and p16 were increased (P < 0.001, P < 0.05). However, the 8-week treadmill exercise reduced the expressions of p53 and p16 proteins (P < 0.05) and increased the level of longevity protein Sirt1 (P < 0.001). In terms of mechanism, the expression level of DKK-1, a negative regulator of Wnt signaling, was increased in the rat hippocampus of the diabetes model group (P < 0.001), while the 8-week treadmill exercise inhibited the expression of DKK-1 (P < 0.001) and reduced the expression levels of Axin1 and β-catenin, downstream key proteins of the Wnt signaling pathway (P < 0.05, P < 0.001). To conclude, treadmill exercise may regulate cell cycle, inhibit apoptosis and promote the secretion of neurotrophic factors by up-regulating the Wnt/β-catenin signaling pathway, thereby improving aging and cognitive impairment in diabetic rats. [ABSTRACT FROM AUTHOR]