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NMR Studies of Brain Energetics & Hypoglycemia In Vivo

脑能量学的核磁共振研究

基本信息

批准号：
7920638
负责人：
KEVIN L BEHAR
金额：
$ 6.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920638
关键词：
2-Fluoro-2-deoxyglucose Accounting Acetates Acids Animals Arts Astrocytes Awareness Blood Brain Carbon Cerebral cortex Chronic Citric Acid Cycle Cognitive Consumption Coupled Diabetes Mellitus Exposure to Frequencies Glucose Glutamate Metabolism Pathway Glutamates Glutamine Glycolysis Grant Housekeeping Hypoglycemia Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intravenous infusion procedures Ketone Bodies Label Laboratories Link Magnetic Resonance Spectroscopy Measures Metabolic Metabolic Pathway Methods Modeling Neocortex Nerve Nervous System Physiology Neurons Neurotransmitters Phosphorylation Physiological Plasma Play Postabsorptive Hypoglycemia Rattus Recurrence Role Testing Up-Regulation Work beta-Hydroxybutyrate cost gamma-Aminobutyric Acid hypoglycemia unawareness in vivo insight neurotransmission oxidation reuptake somatosensory stoichiometry type I diabetic validation studies

项目摘要

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.

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。在某些条件下，例如慢性低血糖，其他血源性底物（一元羧酸）可能会发生大量氧化。然而，替代底物在多大程度上可以替代葡萄糖来支持大脑功能尚不清楚。这个问题对于 1 型糖尿病的治疗非常重要，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 的化学计量耦合。这一发现支持了一个机制模型，该模型可以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进行具体预测。该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。长期暴露于反复性低血糖会导致替代燃料氧化的上调，但不会取代对葡萄糖的强制性需求。这项工作将涉及最先进的体内磁共振波谱 (MRS) 的应用以及 13C 标记底物的静脉输注。我们将评估增加一元羧酸（3-羟基丁酸、乳酸和乙酸）的氧化对大鼠新皮质中葡萄糖利用率与谷氨酸和 GABA 神经递质循环之间关系的影响。这些研究将在生理正常大鼠和复发性低血糖大鼠模型中进行，其中交替底物氧化被认为是上调的。这些研究的结果有望为以下方面提供基本见解：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 型糖尿病患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。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Coupling of glutamatergic neurotransmission and neuronal glucose oxidation over the entire range of cerebral cortex activity.

在整个大脑皮层活动范围内谷氨酸能神经传递和神经元葡萄糖氧化的耦合。

DOI：
10.1196/annals.1300.050
发表时间：
2003
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Patel,AnantB;DeGraaf,RobinA;Mason,GraemeF;Rothman,DouglasL;Shulman,RobertG;Behar,KevinL
通讯作者：
Behar,KevinL

Functional imaging studies: linking mind and basic neuroscience.

功能成像研究：连接心灵和基础神经科学。

DOI：
10.1176/appi.ajp.158.1.11
发表时间：
2001
期刊：
The American journal of psychiatry.
影响因子：
0
作者：
Shulman,RG
通讯作者：
Shulman,RG

Functional MRI BOLD signal coincides with electrical activity in the rat whisker barrels.

功能性 MRI BOLD 信号与大鼠胡须桶中的电活动一致。

DOI：
10.1002/mrm.1910380604
发表时间：
1997
期刊：
Magnetic resonance in medicine
影响因子：
3.3
作者：
Yang,X;Hyder,F;Shulman,RG
通讯作者：
Shulman,RG

Combined 1H and 31P NMR studies of the rat brain in vivo: effects of altered intracellular pH on metabolism.

大鼠脑体内 1H 和 31P NMR 联合研究：细胞内 pH 值改变对代谢的影响。

DOI：
10.1111/j.1749-6632.1987.tb32896.x
发表时间：
1987
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Behar,KL;Rothman,DL;Fitzpatrick,SM;Hetherington,HP;Shulman,RG
通讯作者：
Shulman,RG

1H NMR visibility of mammalian glycogen in solution.

溶液中哺乳动物糖原的 1H NMR 可见度。

DOI：
10.1073/pnas.87.5.1678
发表时间：
1990
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Zang,LH;Rothman,DL;Shulman,RG
通讯作者：
Shulman,RG