Lai Sijie, Kang Zhenghong, Sun Jianting, Wang Ziyu, Xu Yanzi, Xing Sisi, Feng Mengying, Wang Yiyi, Liu Hua
College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China.
Laboratory of Physical Fitness Monitoring & Chronic Disease Intervention, Wuhan Sports University, Wuhan 430079, China.
Brain Sci. 2025 May 1;15(5):480. doi: 10.3390/brainsci15050480.
: Diabetes frequently leads to cognitive impairment, encompassing issues with memory and executive function, as well as depression and anxiety. This study examines the impact of high-intensity interval exercise (HIIE) alongside glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide on cognitive dysfunction associated with diabetes. : Db/db mice were divided into a control group, semaglutide group, HIIE group, and semaglutide combined with HIIE group to study metabolic and neurobehavioral effects. Cognitive and behavioral tests, hippocampal morphology, and molecular analyses (APP, BDNF, Aβ, p-Tau, PKA, AMPK) were performed. HT22 cells under high glucose were treated with semaglutide, L-lactate, PKA inhibitor H89, and AMPK inhibitor Compound C to validate mechanisms. : Over 8 weeks, both HIIE and semaglutide improved neuronal morphology and cognitive performance while reducing depression in db/db mice. However, the current study observed no synergistic effects. Both therapies decreased Aβ and p-Tau protein levels and increased BDNF levels in the hippocampus, likely through the AMPK and PKA signaling pathways, respectively. In vitro, HT22 cells under high glucose conditions exhibited elevated APP and p-Tau expression and reduced BDNF levels, which could be altered by L-lactate and semaglutide. The AMPK inhibitor Compound C and the PKA inhibitor H89 attenuated the increase in BDNF levels induced by L-lactate and semaglutide, but their combination mitigated this inhibitory effect. This study suggests that while HIIE and semaglutide improve cognitive function and reduce depression via BDNF, their combined use did not show the anticipated synergistic benefits due to potential antagonism between the AMPK and PKA pathways. : This has important implications for designing exercise prescriptions for cognitive impairment in diabetics.
糖尿病常常导致认知障碍，包括记忆和执行功能问题，以及抑郁和焦虑。本研究考察了高强度间歇运动（HIIE）与胰高血糖素样肽-1受体激动剂（GLP-1 RA）司美格鲁肽对糖尿病相关认知功能障碍的影响。将db/db小鼠分为对照组、司美格鲁肽组、HIIE组和司美格鲁肽联合HIIE组，以研究代谢和神经行为效应。进行了认知和行为测试、海马形态学分析以及分子分析（APP、BDNF、Aβ、p-Tau、PKA、AMPK）。用司美格鲁肽、L-乳酸、PKA抑制剂H89和AMPK抑制剂化合物C处理高糖环境下的HT22细胞，以验证作用机制。在8周的时间里，HIIE和司美格鲁肽均改善了db/db小鼠的神经元形态和认知表现，同时减轻了抑郁。然而，本研究未观察到协同效应。两种疗法均降低了海马体中Aβ和p-Tau蛋白水平，并提高了BDNF水平，可能分别是通过AMPK和PKA信号通路实现的。在体外，高糖条件下的HT22细胞表现出APP和p-Tau表达升高以及BDNF水平降低，而L-乳酸和司美格鲁肽可以改变这种情况。AMPK抑制剂化合物C和PKA抑制剂H89减弱了L-乳酸和司美格鲁肽诱导的BDNF水平升高，但二者联合使用减轻了这种抑制作用。本研究表明，虽然HIIE和司美格鲁肽通过BDNF改善认知功能并减轻抑郁，但由于AMPK和PKA通路之间可能存在拮抗作用，二者联合使用并未显示出预期的协同益处。这对于为糖尿病患者的认知障碍设计运动处方具有重要意义。
