BACKGROUND: Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and brain structure and function, at least in healthy people, but the impact of exercise training on these aspects remains to be fully elucidated in patients with T2DM. OBJECTIVES: To determine the impact of exercise training on cognition and brain structure and function in T2DM, and identify the involved physiological mediators. METHODS: This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the 14th of January 2025 were searched by means of the electronic databases PubMed, Embase, and Web of Science. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (eg dietary changes, cognitive training, etc.). Study quality was assessed by means of the TESTEX tool for human studies, and the CAMARADES tool for animal studies. RESULTS: For the systematic part of the review, 22 papers were found to be eligible. 18 out of 22 papers (81.8%) showed a significant positive effect of exercise training on cognition in T2DM, of which two studies only showed significant improvements in the minority of the cognitive tests. Four papers (18.2%) could not find a significant effect of exercise on cognition in T2DM. Resistance and endurance exercise were found to be equally effective for achieving cognitive improvement. Machine-based power training is seemingly more effective than resistance training with body weight and elastic bands to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3beta, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on brain structure and function in T2DM. Via these mediators, exercise training induces multiple beneficial brain changes, such as increased neuroplasticity, increased insulin sensitivity, and decreased inflammation. CONCLUSIONS: Overall, exercise training beneficially affects cognition and brain structure and function in T2DM, with resistance and endurance exercise having similar effects. However, there is a need for additional studies, and more methodological consistency between different studies in order to define an exercise program optimal for improving cognition in T2DM. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process. The current body of literature demonstrates a positive effect of exercise training on the brain in T2DM, but simultaneously emphasizes the need for additional studies on this topic. BDNF, lactate, leptin, adiponectin, GSK3beta, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway have been identified as factors mediating the effect of exercise on the brain in T2DM. There is a need for a standardised cognitive test battery to investigate the effect of exercise on cognition in T2DM.

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