Lapidot A, Haber S
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
J Neurosci Res. 2001 Apr 15;64(2):207-16. doi: 10.1002/jnr.1067.
The neurological consequences of diabetes mellitus have recently been receiving greater attention in both clinical and experimental settings. The deleterious effect of hyperglycemia and altered oxidative substrate availability on the diabetic brain is the subject of many studies. The aim of the present study was to examine the effect of the altered metabolic environment, namely, hyperglycemia and hyperketonemia, on glucose metabolism in the diabetic brain. More specifically, we examined the effect of diabetes on the glucose flux via the pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) pathways and subsequent metabolism in the tricarboxylic acid cycles in neurons and glia. To this end, [U-(13)C]glucose was infused into the circulation of alloxan-induced diabetic young adult rabbits, and the [(13)C]glucose metabolites were subsequently studied in brain extracts by (13)C-NMR. Significantly elevated brain glucose levels were found. In the hyperketonemic rabbits, elevated cerebral levels of beta-hydroxybutyrate (beta-HBA) were found. Alterations in the labeling patterns of glutamine in the hyperketonemic group lead to the conclusion that the elevated beta-HBA levels inhibit glucose metabolism, mostly in glia. This results in accumulation of glucose in the diabetic brain. In addition, altered levels of glutamine, glutamate, and GABA were also attributed to the effect of beta-HBA on brain metabolism. The possible role of these metabolic perturbations in causing neurological damage remains to be investigated.
糖尿病的神经学后果最近在临床和实验环境中都受到了更多关注。高血糖和氧化底物可用性改变对糖尿病大脑的有害影响是许多研究的主题。本研究的目的是检查代谢环境改变，即高血糖和高酮血症，对糖尿病大脑葡萄糖代谢的影响。更具体地说，我们研究了糖尿病对通过丙酮酸脱氢酶（PDH）和丙酮酸羧化酶（PC）途径的葡萄糖通量以及随后在神经元和神经胶质细胞三羧酸循环中的代谢的影响。为此，将[U-(13)C]葡萄糖注入四氧嘧啶诱导的糖尿病成年幼兔的循环系统中，随后通过(13)C-NMR在脑提取物中研究[(13)C]葡萄糖代谢物。发现脑葡萄糖水平显著升高。在高酮血症兔中，发现脑β-羟基丁酸（β-HBA）水平升高。高酮血症组谷氨酰胺标记模式的改变得出结论，即升高的β-HBA水平抑制葡萄糖代谢，主要是在神经胶质细胞中。这导致糖尿病大脑中葡萄糖的积累。此外，谷氨酰胺、谷氨酸和γ-氨基丁酸水平的改变也归因于β-HBA对脑代谢的影响。这些代谢紊乱在导致神经损伤中的可能作用仍有待研究。
