Chen Lei, Liu Run, He Xin, Fang Jiacheng, Zhou Liyin, Qi Zhongshi, Tao Mingzhu, Yuan Haicheng, Zhou Yu
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China.
School of Public Health, Qingdao University, Qingdao, Shandong Province, China.
Clin Nutr. 2025 Feb;45:111-123. doi: 10.1016/j.clnu.2025.01.002. Epub 2025 Jan 6.
Diabetic cognitive dysfunction (DCD) refers to the cognitive impairment observed in individuals with diabetes. Epidemiological studies have suggested that supplementation with n-3 polyunsaturated fatty acid (PUFA) or B vitamins may prevent the development of diabetic complications. Post hoc studies indicate a potential synergistic effect of n-3 PUFA and B vitamins in preventing cognitive impairment. However, the precise effect and underlying mechanism of this combination on DCD remain unclear. In case-control study, we compared fatty acid composition of erythrocyte membrane and serum homocysteine levels between diabetic individuals with and without DCD. We found that insufficient levels of n-3 PUFA, along with elevated serum homocysteine, significantly increase the risk of developing DCD. Treatment with a combination of fish oil, folate, and vitamin B improved cognitive impairment and aberrant neuronal morphology in streptozotocin-induced DCD mice. Folic acid and vitamin B enhanced the efficiency of exogenous docosahexaenoic acid (DHA) transportation to the brain by preventing the accumulation of homocysteine and S-adenosylhomocysteine, thereby inhibiting neuronal apoptosis in diabetic brains. Furthermore, folic acid and vitamin B supplementation can provide sufficient 5-methylcytosine for diabetic brains by promoting DNA methylation, while increased DHA levels maintain TET-mediated active DNA demethylation in diabetic brains through enhancing TET2 function. Overall, our study provides novel insights into molecular mechanisms underlying the synergistic preventive effects of the combined supplementation with fish oil, folic acid and vitamin B on DCD, suggests that combining n-3 PUFA and B vitamins could be a promising strategy for preventing DCD among individuals with diabetes.
糖尿病认知功能障碍（DCD）是指在糖尿病患者中观察到的认知损害。流行病学研究表明，补充n-3多不饱和脂肪酸（PUFA）或B族维生素可能预防糖尿病并发症的发生。事后分析研究表明，n-3 PUFA和B族维生素在预防认知损害方面具有潜在的协同作用。然而，这种组合对DCD的确切作用和潜在机制仍不清楚。在病例对照研究中，我们比较了有和没有DCD的糖尿病个体的红细胞膜脂肪酸组成和血清同型半胱氨酸水平。我们发现，n-3 PUFA水平不足以及血清同型半胱氨酸升高会显著增加发生DCD 的风险。用鱼油、叶酸和维生素B的组合治疗可改善链脲佐菌素诱导的DCD小鼠的认知损害和异常神经元形态。叶酸和维生素B通过防止同型半胱氨酸和S-腺苷同型半胱氨酸的积累，提高外源性二十二碳六烯酸（DHA）向大脑转运的效率，从而抑制糖尿病大脑中的神经元凋亡。此外，补充叶酸和维生素B可通过促进DNA甲基化，为糖尿病大脑提供足够的5-甲基胞嘧啶，而升高的DHA水平则通过增强TET2功能维持糖尿病大脑中TET介导的活性DNA去甲基化作用。总体而言，我们的研究为鱼油、叶酸和维生素B联合补充对DCD的协同预防作用的潜在分子机制提供了新见解，表明联合n-3 PUFA和B族维生素可能是预防糖尿病患者发生DCD的一种有前景的策略。
