Human Brain Ketone Metabolism in Type 1 Diabetes and Hypoglycemia.

1 型糖尿病和低血糖中的人脑酮代谢。

基本信息

批准号：
8779720
负责人：
Raimund Ingo Herzog
金额：
$ 8.1万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8779720
关键词：
Acetates Acids Acute Address Age Animal Model Blood - brain barrier anatomy Blood Glucose Blood specimen Brain Brain Injuries Butyrates Carbon Carrier Proteins Catecholamines Cessation of life Child Citric Acid Cycle Complications of Diabetes Mellitus Cross-Over Studies Data Development Diabetes Mellitus Energy Metabolism Exposure to Failure Fasting Functional disorder Glucagon Glucose Glutamates Goals Health Homeostasis Hormonal Human Hydroxybutyrates Hypoglycemia Impaired cognition Impairment In Vivo NMR Spectroscopy Incidence Individual Infusion procedures Injury Insulin Insulin-Dependent Diabetes Mellitus Isotope Labeling Ketone Bodies Ketones Life Magnetic Resonance Spectroscopy Measurement Measures Metabolic Metabolism NMR Spectroscopy Neurons Neurotransmitters Outcome Patients Positioning Attribute Prevention strategy Production Protons Recurrence Research Design Risk Rodent Model Role Sleep Symptoms Testing Treatment Protocols Ursidae Family adverse outcome base beta-Hydroxybutyrate blood glucose regulation brain metabolism cognitive function diabetic diabetic patient experience gamma-Aminobutyric Acid glycemic control healthy volunteer human subject hypoglycemia unawareness improved in vivo novel novel therapeutic intervention protein expression 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. This proposal is aimed at characterizing the CNS complications of intensive insulin therapy in type 1 diabetes; specifically, abnormalities in brain metabolism and its adaptations to recurrent hypoglycemia, the major cause of hypoglycemia unawareness. Previous data from our group from type 1 diabetic patients showed an increased ability of the brain to utilize alternate fuels under hypoglycemia, likely due to increased transporter protein expression. Preliminary in vivo NMR spectroscopy data from our animal model of recurrent hypoglycemia confirmed these findings since we found that infused monocarboxylic acids such as acetate and lactate could serve as energy substrates other than glucose and support brain metabolism under hypoglycemia. Antecedent recurrent hypoglycemia enhances these effects via a functional increase in alternate fuel transport into the brain. When testing lactate as an alternative fuel, we made the surprising observation that even though its uptake following exposure to recurrent hypoglycemia was enhanced, it still did not contribute significantly to overall brain oxidative capacity. Together this led us to hypothesize that recurrent hypoglycemia enhances uptake of monocarboxylic acids into the brain, which could be taken advantage of to support neuronal metabolism if a candidate fuel would not be subject to the same limitations as lactate. Because it does not depend on the potentially limiting step of pyruvate dehydrogenase conversion, beta-hydroxy-butyrate is one such fuel. Thus, we are proposing to determine the ability of the neuronal fuel beta-hydroxy-butyrate to support metabolic fluxes and to support human brain energy homeostasis under hypoglycemia. In a crossover study design, we will characterize brain ketone metabolism by carbon-13 NMR spectroscopy in healthy control and type 1 diabetic subjects during eu- and hypoglycemic clamp studies. By providing an alternate fuel when glucose is in limited supply, we will then be in the position to determine the contribution of ketones to overall brain metabolism. We will also characterize the ketone effect on neurotransmitter homeostasis. Our data will refine our understanding of brain monocarboxylic acid metabolism and will have important implications for creating new therapies to reduce brain dysfunction, injury and even death from hypoglycemia. Perhaps more importantly, this novel therapy may provide the opportunity to achieve tighter glucose control of type 1 diabetic patients, with reduced risk of brain injury from severe hypoglycemia, thus allowing more aggressive treatment and decreasing long term complications.

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。该提案旨在描述 1 型糖尿病强化胰岛素治疗的中枢神经系统并发症的特征；具体来说，大脑代谢异常及其对反复低血糖的适应，是低血糖无意识的主要原因。我们小组之前对 1 型糖尿病患者的数据显示，在低血糖情况下，大脑利用替代燃料的能力有所增强，这可能是由于转运蛋白表达增加所致。我们的复发性低血糖动物模型的初步体内核磁共振波谱数据证实了这些发现，因为我们发现注入的一元羧酸（例如乙酸盐和乳酸）可以作为葡萄糖以外的能量底物，并支持低血糖下的脑代谢。先前的反复低血糖通过增加向大脑的替代燃料运输的功能来增强这些影响。当测试乳酸作为替代燃料时，我们得出了令人惊讶的观察结果，即尽管反复低血糖后乳酸的吸收有所增强，但它仍然对整体大脑氧化能力没有显着贡献。总之，我们推测，反复性低血糖会增强大脑对单羧酸的吸收，如果候选燃料不会受到与乳酸相同的限制，则可以利用这一点来支持神经元代谢。因为它不依赖于丙酮酸脱氢酶转化的潜在限制步骤，β-羟基丁酸就是这样的燃料之一。因此，我们建议确定神经元燃料β-羟基丁酸酯支持代谢通量和支持低血糖下人脑能量稳态的能力。在交叉研究设计中，我们将在欧盟和低血糖钳夹研究期间通过碳 13 NMR 光谱来表征健康对照和 1 型糖尿病受试者的脑酮代谢。通过在葡萄糖供应有限时提供替代燃料，我们将能够确定酮对整体大脑代谢的贡献。我们还将描述酮对神经递质稳态的影响。我们的数据将加深我们对大脑单羧酸代谢的理解，并将对创造新疗法以减少脑功能障碍、损伤甚至低血糖死亡具有重要意义。也许更重要的是，这种新疗法可能为 1 型糖尿病患者提供更严格的血糖控制的机会，降低严重低血糖导致脑损伤的风险，从而允许更积极的治疗并减少长期并发症。