Dept. of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
Neurochem Int. 2012 Feb;60(3):267-75. doi: 10.1016/j.neuint.2011.12.019. Epub 2012 Jan 5.
The number of people suffering from diabetes is hastily increasing and the condition is associated with altered brain glucose homeostasis. Brain glycogen is located in astrocytes and being a carbohydrate reservoir it contributes to glucose homeostasis. Furthermore, glycogen has been indicated to be important for proper neurotransmission under normal conditions. Previous findings from our laboratory suggested that glucose metabolism was reduced in type 2 diabetes, and thus we wanted to investigate more specifically how brain glycogen metabolism contributes to maintain energy status in the type 2 diabetic state. Also, our objective was to elucidate the contribution of glycogen to support neurotransmitter glutamate and GABA homeostasis. A glycogen phosphorylase (GP) inhibitor was administered to Sprague-Dawley (SprD) and Zucker Diabetic Fatty (ZDF) rats in vivo and after one day of treatment [1-¹³C]glucose was used to monitor metabolism. Brain levels of ¹³C labeling in glucose, lactate, alanine, glutamate, GABA, glutamine and aspartate were determined. Our results show that inhibition of brain glycogen metabolism reduced the amounts of glutamate in both the control and type 2 diabetes models. The reduction in glutamate was associated with a decrease in the pyruvate carboxylase/pyruvate dehydrogenase ratio in the control but not the type 2 diabetes model. In the type 2 diabetes model GABA levels were increased suggesting that brain glycogen serves a role in maintaining a proper ratio between excitatory and inhibitory neurotransmitters in type 2 diabetes. Both the control and the type 2 diabetic states had a compensatory increase in glucose-derived ¹³C processed through the TCA cycle following inhibition of glycogen degradation. Finally, it was indicated that the type 2 diabetes model might have an augmented necessity for compensatory upregulation at the glycolytic level.
患糖尿病的人数正在迅速增加，该病症与大脑葡萄糖稳态的改变有关。脑糖原位于星形胶质细胞中，作为碳水化合物的储存库，它有助于葡萄糖稳态。此外，糖原已被证明在正常条件下对于适当的神经递质传递很重要。我们实验室的先前发现表明，2 型糖尿病患者的葡萄糖代谢减少，因此我们想更具体地研究脑糖原代谢如何有助于维持 2 型糖尿病状态下的能量状态。此外，我们的目的是阐明糖原对支持神经递质谷氨酸和 GABA 稳态的贡献。体内给予 Sprague-Dawley (SprD) 和 Zucker 糖尿病肥胖 (ZDF) 大鼠糖原磷酸化酶 (GP) 抑制剂，并在治疗 1 天后使用 [1-¹³C]葡萄糖监测代谢。测定葡萄糖、乳酸、丙氨酸、谷氨酸、GABA、谷氨酰胺和天冬氨酸中¹³C 标记的脑水平。我们的结果表明，抑制脑糖原代谢减少了两种对照和 2 型糖尿病模型中的谷氨酸含量。谷氨酸的减少与对照模型中丙酮酸羧化酶/丙酮酸脱氢酶的比值降低有关，但在 2 型糖尿病模型中没有降低。在 2 型糖尿病模型中，GABA 水平升高表明，在 2 型糖尿病中，脑糖原在维持兴奋性和抑制性神经递质之间的适当比例方面发挥作用。抑制糖原降解后，对照和 2 型糖尿病状态下通过 TCA 循环处理的葡萄糖衍生¹³C 均有代偿性增加。最后，表明 2 型糖尿病模型可能在糖酵解水平上需要代偿性上调。
