González Pérez Nicolás, Bellotto Melina, Porte Alcón Soledad, Bentivegna Melisa, Arcucci Luciano, Vinuesa Ángeles, Presa Jessica, Brites Fernando, Pérez Sirkin Daniela, Beauquis Juan, Saravia Flavia, Pomilio Carlos
Instituto de Biología y Medicina Experimental (CONICET), Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Life Sci. 2025 Oct 1;378:123803. doi: 10.1016/j.lfs.2025.123803. Epub 2025 Jun 8.
The rising prevalence of type 2 diabetes (T2D), obesity, and metabolic syndrome highlights the need for therapeutic strategies addressing both metabolic and neurological aspects of these conditions. This study evaluates the potential of metformin, a widely prescribed antidiabetic drug, to mitigate hippocampal changes induced by a moderate high-fat diet (HFD) and explores its mechanisms beyond glycemic regulation, including modulation of microglial autophagy, mitochondrial turnover, and neuroinflammation.
We analyzed data from diabetic patients enrolled in the NACC study, a retrospective observational study, to assess cognitive outcomes associated with metformin use. Additionally, we examined the effects of metformin in HFD-treated mice, evaluating hippocampal insulin resistance, synaptic marker and microglial status. We also employed BV2 microglial cells exposed to palmitate as a lipotoxic stimulus to assess the potential of metformin in modulating microglial autophagy, mitochondrial status and inflammatory response.
In diabetic patients, metformin use is associated with improved memory and executive function, independent of cardiovascular risk factor control. In HFD-treated mice, metformin reduced hippocampal insulin resistance, increased synaptophysin levels, and reversed microglial activation and autophagy impairment. In BV2 microglial cells, metformin reduced IL-1β and TNFα expression, restored autophagic flux, and regulated mitochondrial turnover, leading to decreased mitochondrial ROS production.
Our findings suggest that metformin exerts therapeutic effects beyond glycemic control in the context of T2D. By mitigating neuroinflammation and modulating microglial autophagy, metformin emerges as a promising therapeutic agent for cognitive decline associated with diabetes and potentially other neurological disorders.
2型糖尿病（T2D）、肥胖症和代谢综合征的患病率不断上升，凸显了针对这些病症的代谢和神经方面制定治疗策略的必要性。本研究评估了广泛使用的抗糖尿病药物二甲双胍减轻中度高脂饮食（HFD）诱导的海马体变化的潜力，并探讨了其血糖调节以外的机制，包括对小胶质细胞自噬、线粒体更新和神经炎症的调节。
我们分析了纳入NACC研究的糖尿病患者的数据，这是一项回顾性观察研究，以评估与二甲双胍使用相关的认知结果。此外，我们研究了二甲双胍对HFD处理小鼠的影响，评估海马体胰岛素抵抗、突触标记物和小胶质细胞状态。我们还使用暴露于棕榈酸酯的BV2小胶质细胞作为脂毒性刺激物，以评估二甲双胍调节小胶质细胞自噬、线粒体状态和炎症反应的潜力。
在糖尿病患者中，二甲双胍的使用与记忆力和执行功能的改善相关，与心血管危险因素控制无关。在HFD处理的小鼠中，二甲双胍降低了海马体胰岛素抵抗，增加了突触素水平，并逆转了小胶质细胞激活和自噬损伤。在BV2小胶质细胞中，二甲双胍降低了IL-1β和TNFα的表达，恢复了自噬通量，并调节了线粒体更新，导致线粒体ROS产生减少。
我们的研究结果表明，在T2D背景下，二甲双胍具有超出血糖控制的治疗作用。通过减轻神经炎症和调节小胶质细胞自噬，二甲双胍成为一种有前景的治疗药物，可用于治疗与糖尿病及潜在其他神经疾病相关的认知衰退。
