Impaired Hippocampal Glutamate and Glutamine Metabolism in the db/db Mouse Model of Type 2 Diabetes Mellitus.
Impaired Hippocampal Glutamate and Glutamine Metabolism in the db/db Mouse Model of Type 2 Diabetes Mellitus.
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DOI：
10.1155/2017/2107084
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发表时间：
2017
影响因子：
3.1
通讯作者：
Waagepetersen HS
中科院分区：
文献类型：
--
作者：
Andersen JV;Nissen JD;Christensen SK;Markussen KH;Waagepetersen HS
2型糖尿病（T2 DM）是阿尔茨海默病发展的危险因素，脑能量代谢的变化已被认为是一种致病机制。本研究旨在研究2型糖尿病db/db小鼠模型中重要氨基酸谷氨酸和谷氨酰胺的脑代谢。谷氨酸和谷氨酰胺都是线粒体氧化的底物，通过Seahorse XFe 96分析在分离的脑线粒体中评估氧消耗。此外，急性分离的大脑皮层和海马切片与[U-13 C]谷氨酸和[U-13 C]谷氨酰胺孵育，并通过气相色谱-质谱法分析组织提取物。以谷氨酸和谷氨酰胺为底物的耗氧率在db/db小鼠的分离脑线粒体中与对照组相比没有差异。db/db小鼠的海马切片显示[U-13 C]谷氨酸代谢引起的谷氨酸、谷氨酰胺、GABA、柠檬酸和天冬氨酸的13 C标记显著减少。此外，与对照组相比，db/db小鼠海马切片中[U-13 C]谷氨酰胺代谢产生的GABA、柠檬酸盐和天冬氨酸盐中的13 C标记减少。在大脑皮质切片中未观察到这些变化。结果表明，在db/db小鼠中，谷氨酸和谷氨酰胺代谢的特定海马损伤，而不影响这些底物的线粒体氧化。
Type 2 diabetes mellitus (T2DM) is a risk factor for the development of Alzheimer's disease, and changes in brain energy metabolism have been suggested as a causative mechanism. The aim of this study was to investigate the cerebral metabolism of the important amino acids glutamate and glutamine in the db/db mouse model of T2DM. Glutamate and glutamine are both substrates for mitochondrial oxidation, and oxygen consumption was assessed in isolated brain mitochondria by Seahorse XFe96 analysis. In addition, acutely isolated cerebral cortical and hippocampal slices were incubated with [U-13C]glutamate and [U-13C]glutamine, and tissue extracts were analyzed by gas chromatography-mass spectrometry. The oxygen consumption rate using glutamate and glutamine as substrates was not different in isolated cerebral mitochondria of db/db mice compared to controls. Hippocampal slices of db/db mice exhibited significantly reduced 13C labeling in glutamate, glutamine, GABA, citrate, and aspartate from metabolism of [U-13C]glutamate. Additionally, reduced 13C labeling were observed in GABA, citrate, and aspartate from [U-13C]glutamine metabolism in hippocampal slices of db/db mice when compared to controls. None of these changes were observed in cerebral cortical slices. The results suggest specific hippocampal impairments in glutamate and glutamine metabolism, without affecting mitochondrial oxidation of these substrates, in the db/db mouse.