FOXO3 and type 2 diabetes mellitus: One-way ANOVA and Tukey post-hoc tests were used to analyze the data.<h4>Results</h4>Serum and hippocampal levels of lactate as well as hippocampal levels of MCT2, SIRT1, FOXO3, LC3, PINK1, Parkin, and antioxidant enzymes were higher while hippocampal levels of Aβ, TAU, and MDA were lower in T2D+EX compared to T2D group (<i>P</i>-value<0.05).<h4>Conclusion</h4>HIIT could improve mitophagy through Lactate-SIRT1-FOXO3-PINK1/Parkin signaling in the hippocampus of rats with T2D reducing the accumulation of Tau and Aβ, which may reduce the risk of memory impairments.