NMR Studies of Brain Energetics & Hypoglycemia In Vivo

描述(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，例如慢性低血糖，其他血液中的底物(单羧酸)会发生大量氧化。然而，替代底物可以在多大程度上取代葡萄糖来支持大脑功能尚不清楚。这个问题在1型糖尿病的治疗中很重要，在1型糖尿病中，低血糖会损害认知和神经功能。本实验室的研究表明，大脑皮层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几乎是1：1的化学计量比。这一发现支持了一个机制模型，该模型导致了关于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可能扮演的角色的具体预测。这一建议的中心假设是，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。长期暴露在反复低血糖会导致替代燃料氧化的上调，但并不能取代对葡萄糖的必需需求。这项工作将涉及在活体磁共振波谱(MRS)中应用最先进的技术，并结合静脉注射13C标记的底物。我们将评估增加一元羧酸(3-羟基丁酸盐、乳酸和醋酸盐)氧化对葡萄糖利用率与大鼠大脑皮层谷氨酸和GABA神经递质循环之间的关系的影响。这些研究将在生理正常的大鼠和反复低血糖的大鼠模型中进行，在那里交替底物氧化被认为是上调的。这些研究的结果有望对葡萄糖在大脑功能中的作用、替代底物在慢性低血糖中的重要性以及这些底物在1型糖尿病患者强化胰岛素治疗过程中可能出现的“无意识低血糖”现象中所起的作用提供基本的见解。

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.