The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high-fat diet (HFD), inducing insulin-resistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.

癫痫和2型糖尿病（T2DM）和/或代谢综合征（MetS）之间的联系尚未得到充分研究。因此，我们测试了高脂饮食（HFD）是否会在小鼠中诱发胰岛素抵抗性糖尿病和肥胖症，从而增加由戊戊四唑（PTZ）引发的全身性癫痫发作的易感性。此外，还研究了与葡萄糖脑运输有关的分子机制和T2DM抗糖尿病药物二甲双胍的作用，以及神经精神病合并症。为此，在CD1小鼠中进行了两组实验，其中我们首先评估了HFD对某些代谢和行为参数的影响，以便为我们的方案第二部分中评估的点燃实验提供基线参考。我们检测到HFD在PTZ点燃模型中易诱发癫痫发作，这与人GLUT-1缺乏症候群中观察到的葡萄糖转运蛋白1（GLUT-1）表达减少有关，但伴随着表达的补偿性增加GLUT-3。尽管我们证实了HFD可以在所治疗的小鼠中诱发神经精神病学改变，但它并未改变点燃合并症的发展。此外，我们建议观察到的二甲双胍对癫痫发作的有益作用与GLUT-1和GLUT-3表达水平的正常化有关。总的来说，我们的结果支持这样的假设：糖代谢谱的改变可能在人类患者中起癫痫的作用。