Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Neurochem Int. 2021 Feb;143:104941. doi: 10.1016/j.neuint.2020.104941. Epub 2020 Dec 15.
Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment.
1 型糖尿病（T1D）已被报道可导致认知功能下降，但在此过程中大脑代谢变化仍远未被充分了解。在这里，我们发现链脲佐菌素（STZ）诱导的 T1D 小鼠在 STZ 治疗后 11 周表现出学习和记忆受损，但在 3 周时没有。因此，我们研究了有认知障碍和无认知障碍的 T1D 小鼠 6 个不同脑区的代谢变化，并试图确定与糖尿病认知功能障碍相关的关键代谢途径。结果表明，在认知障碍发生之前，T1D 小鼠的所有脑区的乳酸水平已经升高，但只有在有认知障碍的 T1D 小鼠的海马体、皮质和纹状体中才观察到 TCA 循环减少。T1D 小鼠的所有脑区的 N-乙酰天冬氨酸和胆碱均减少，无论是否存在认知障碍。此外，在认知缺陷发生之前，就已经注意到 T1D 小鼠的神经递质代谢紊乱。值得注意的是，当出现认知衰退时，我们发现 T1D 小鼠小脑、皮质、下丘脑和中脑的尿苷水平显著降低。因此，大脑区域特异性代谢变化可能成为糖尿病认知衰退早期诊断和监测的潜在生物标志物。此外，TCA 循环和嘧啶代谢下调可能与 T1D 相关的认知障碍密切相关。
