NMR Studies of Brain Energetics & Hypoglycemia In Vivo

描述（由申请人提供）：葡萄糖是大脑的主要底物，其中大部分在神经元中被氧化，提供功能活动所需的能量。在某些情况下，如慢性低血糖，其他血液传播的底物（单羧酸）可能发生大量氧化。然而，替代底物可以在多大程度上取代葡萄糖以支持脑功能尚不清楚。这个问题在1型糖尿病的治疗中非常重要，因为低血糖会损害认知和神经功能。该实验室的研究表明，大脑皮层中的神经元葡萄糖氧化与神经元和星形胶质细胞之间的谷氨酸/GABA/谷氨酰胺神经递质循环以接近1：1的化学计量偶联。这一发现支持了一种机制模型，该模型导致对葡萄糖在支持神经递质循环中的基本作用以及替代底物作为氧化燃料的作用的具体预测。这个提议的中心假设是，星形胶质细胞糖酵解是谷氨酸/GABA循环的功能支持所必需的，但神经元葡萄糖氧化可以被其他燃料取代。长期暴露于复发性低血糖导致替代燃料氧化的上调，但不能取代对葡萄糖的强制性需求。这项工作将涉及应用最先进的体内磁共振光谱（MRS）结合静脉输注13 C标记的底物。我们将评估增加氧化的单羧酸（3-羟基丁酸，乳酸和乙酸）的葡萄糖利用率和神经递质循环的谷氨酸和GABA在大鼠新皮层之间的关系的影响。研究将在生理正常大鼠和反复低血糖大鼠模型中进行，其中认为交替底物氧化上调。这些研究的结果有望为葡萄糖在脑功能中的作用、替代底物作为慢性低血糖燃料的重要性以及这些底物在1型糖尿病受试者强化胰岛素治疗期间可能出现的“低血糖无意识”现象中可能发挥的作用提供基本见解。

DESCRIPTION (provided by applicant): Glucose is the primary substrate of the brain and most of this is oxidized in neurons providing the energy required for functional activity. Under certain conditions, such as chronic hypoglycemia, substantial oxidation of other blood-borne substrates (monocarboxylic acids) can occur. The extent to which alternate substrates can replace glucose in support of brain function however is not known. This issue is of importance in the treatment of type-1 diabetes where hypoglycemia can compromise cognitive and neurological function. Studies in this laboratory have shown that neuronal glucose oxidation in the cerebral cortex is coupled to glutamate/GABA/glutamine neurotransmitter cycling between neurons and astroglia in a near 1:1 stoichiometry. This finding supports a mechanistic model which leads to specific predictions about the fundamental role of glucose in the support of neurotransmitter cycling and the role that alternate substrates could play as oxidative fuels. The central hypothesis of this proposal is that astroglial glycolysis is required for functional support of glutamate/GABA cycling but that neuronal glucose oxidation can be replaced by other fuels. Prolonged exposure to recurrent-hypoglycemia leads to up-regulation of alternate fuel oxidation but does not replace the obligatory need for glucose. The work will involve the application of state-of-the-art In Vivo Magnetic Resonance Spectroscopy (MRS) in conjunction with intravenous infusions of 13C-labeled substrates. We will assess the effects of increasing oxidation of monocarboxylic acids (3-hydroxybutyrate, lactate, and acetate) on the relationship between the rates of glucose utilization and neurotransmitter cycling of glutamate and GABA in the rat neocortex. The studies will be conducted in physiological normal rats and in a rat model of recurrent-hypoglycemia where alternate substrate oxidation is believed to be up-regulated. Results of these studies can be expected to provide fundamental insights into the role of glucose in brain function, the importance of alternate substrate as fuels in chronic hypoglycemia, and the role that these substrates may play in the phenomenon of 'hypoglycemia unawareness' which can arise during intensive insulin therapy in subjects with type-1 diabetes.