Adaptations of Brain Energy Metabolism to Hypoglycemia

脑能量代谢对低血糖的适应

基本信息

批准号：
8720524
负责人：
Raimund Ingo Herzog
金额：
$ 10.42万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720524
关键词：
Acetates Acute Address Animal Model Animals Award Basic Science Blood Glucose Brain Brain Injuries Caprylates Carbohydrates Carbon Chronic Citric Acid Cycle Clinical Clinical Research Cognition Cognitive Complications of Diabetes Mellitus Data Dependence Deterioration Development Diabetes Mellitus Diet Dietary Intervention Energy Metabolism Enrollment Exposure to Failure Fellowship Fright Funding Glucose Goals Health Health Sciences Hormones Human Hyperglycemia Hypoglycemia Impaired cognition In Vivo NMR Spectroscopy Incidence Infusion procedures Injury Insulin Insulin-Dependent Diabetes Mellitus Investigation Ketone Bodies Ketones Label Laboratories Measures Medium chain fatty acid Metabolic Metabolism Methods Microvascular Dysfunction Mind Mitochondria NMR Spectroscopy National Research Service Awards Neurons Neurosciences Pathway interactions Patients Performance Physicians Physiological Plasma Pyruvate Dehydrogenase Complex Recurrence Risk Route Scanning Scientist Stimulus Symptoms Technology Testing Therapeutic Uses Time Tissues Training Translating Ursidae Family Work animal data base blood glucose regulation brain metabolism career cognitive function diabetic diabetic patient diabetic rat follow-up human subject hypoglycemia unawareness improved in vivo macrovascular disease metabolic abnormality assessment neuroprotection neurotransmitter metabolism novel novel therapeutic intervention novel therapeutics prevent programs pyruvate dehydrogenase response type I diabetic uptake

项目摘要

DESCRIPTION (provided by applicant): Diabetic complications can be reduced by normalization of blood glucose levels via intensive insulin therapy. This treatment, while effective, bears the risk of an increased incidence of recurrent hypoglycemia. It blunts the central counterregulatory response to low blood glucose (counterregulatory failure) and thereby magnifies the risk of severe hypoglycemia and brain injury. The overall goal of this proposal is to understand the changes in brain metabolism that underlie these phenomena and identify possible therapies in order to prevent them. We will determine the impact of a medium chain fatty acid enriched diet on brain metabolism in tightly controlled T1DM subjects with hypoglycemia unawareness and an animal model thereof. We will further test the hypothesis that chronic provision of medium chain fatty acids can improve cognitive performance under hypoglycemia in human subjects. Data gathered from our animal studies revealed a specific change of neuronal energy metabolism under hypoglycemia following exposure to antecedent recurrent hypoglycemia that make is more difficult for neurons to utilize fuels like glucose or lactate. We also found that after recurrent hypoglycemia, lactate uptake into the brain was facilitated, but because it could subsequently not be utilized by mitochondria as effectively as under control conditions, it may not be an ideal fuel. This let us to look for different alternate substrates that follow the same route of uptake as lactate, but enter metabolism via a different pathway. One group of fuels that fulfill these criteria are ketone bodies and medium chain fatty acids. Applying state of the art technologies like in vivo NMR spectroscopy to our animal model of recurrent hypoglycemia will allows us address the hypothesis that they are better suited to support metabolism. We will use this animal model to determine how diabetes confounds the adaptations induced by recurrent hypoglycemia alone and then go on to translate our findings to a clinical study of cognition and metabolism in intensively treated T1DM patients. Our work is the first step towards developing candidate molecules into novel therapies that would protect the brain from hypoglycemia induced brain injury. The projects proposed here are building on preliminary studies that I have performed during my NRSA fellowship training and since then. They will give me the ideal opportunity to continue my training in NMR spectroscopy and its application to neuroscience and diabetes related complications. Most of my training thus far has been in the use of basic science methods and animal models. Wanting to become a well trained physician scientist however I realized that I still needed more training in human investigation. To that end I enrolled in a Master of Health Sciences program to receive further training in translational methods. Funding under this career award will allow me to continue these activities and give me the protected time from clinical duties that I will need to accomplish my career goal of establishing myself as an independently funded physician-scientist, eventually with my own laboratory and workgroup.

描述（由申请人提供）：通过强化胰岛素治疗使血糖水平正常化可以减少糖尿病并发症。这种治疗虽然有效，但存在反复低血糖发生率增加的风险。它削弱了中枢对低血糖的反调节反应（反调节失败），从而增加了严重低血糖和脑损伤的风险。该提案的总体目标是了解这些现象背后的大脑代谢变化，并找出可能的治疗方法来预防它们。我们将确定富含中链脂肪酸的饮食对患有低血糖且严格控制的 T1DM 受试者及其动物模型的脑代谢的影响。我们将进一步检验以下假设：长期提供中链脂肪酸可以改善人类受试者在低血糖情况下的认知能力。从我们的动物研究中收集的数据显示，在暴露于先前的反复低血糖之后，低血糖下神经元能量代谢发生了特定的变化，这使得神经元更难以利用葡萄糖或乳酸等燃料。我们还发现，反复发生低血糖后，大脑对乳酸的吸收得到了促进，但由于它随后不能像控制条件下那样有效地被线粒体利用，因此它可能不是理想的燃料。这让我们能够寻找不同的替代底物，它们遵循与乳酸相同的吸收途径，但通过不同的途径进入代谢。满足这些标准的一组燃料是酮体和中链脂肪酸。将体内核磁共振波谱等最先进的技术应用于我们的复发性低血糖动物模型将使我们能够解决这样的假设：它们更适合支持新陈代谢。我们将使用该动物模型来确定糖尿病如何混淆仅由反复低血糖引起的适应，然后将我们的发现转化为针对接受强化治疗的 T1DM 患者的认知和代谢的临床研究。我们的工作是将候选分子开发成新疗法的第一步，以保护大脑免受低血糖引起的脑损伤。这里提出的项目是建立在我在 NRSA 奖学金培训期间及此后进行的初步研究的基础上的。他们将为我提供理想的机会，继续我的核磁共振波谱学培训及其在神经科学和糖尿病相关并发症中的应用。到目前为止，我的大部分培训都是使用基础科学方法和动物模型。我想成为一名训练有素的医学科学家，但我意识到我仍然需要更多的人类研究培训。为此，我参加了健康科学硕士课程，接受转化方法方面的进一步培训。该职业奖的资助将使我能够继续这些活动，并为我提供免受临床职责的保护时间，以实现我的职业目标，即使自己成为一名独立资助的医师科学家，最终拥有自己的实验室和工作组。