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的血糖水平标准化可以减少糖尿病并发症。这种治疗虽然有效，但仍有增加复发性低血糖症发生率的风险。它钝化了对低血糖（反调节衰竭）的中心反应反应，从而放大了严重低血糖和脑损伤的风险。该建议旨在表征1型糖尿病中强化胰岛素治疗的中枢神经系统并发症。具体来说，脑代谢异常及其对复发性低血糖的适应性，这是低血糖不认识的主要原因。 1型糖尿病患者我们组的先前数据显示，大脑在低血糖下使用替代燃料的能力提高，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症动物模型的初步体内NMR光谱数据证实了这些发现，因为我们发现注入的单羧酸（例如乙酸和乳酸）可以用作葡萄糖以外的能量底物，并支持低血糖下的葡萄糖和支持脑代谢。先前的复发性低血糖通过替代燃料转运到大脑的功能增加来增强这些影响。当将乳酸作为替代燃料测试时，我们令人惊讶地观察到，即使暴露于复发性低血糖后其吸收增强了，但它仍然没有对整体脑氧化能力产生重大贡献。这共同导致我们假设复发性低血糖增强了单羧酸对大脑的摄取，如果候选燃料不受乳酸相同的限制，则可以利用它来支持神经元代谢。由于它不取决于丙酮酸脱氢酶转化的潜在限制步骤，因此β-羟基丁酸是这样的燃料。因此，我们提议确定神经元燃料β-羟基丁酸支持代谢通量并支持低血糖下的人脑能量稳态的能力。在跨界研究设计中，我们将在欧盟和降血糖夹具研究期间通过碳-13 NMR光谱在健康对照和1型糖尿病受试者中通过碳13 NMR光谱的脑酮代谢表征。通过在葡萄糖供应有限时提供替代燃料，我们将有能力确定酮对整体脑代谢的贡献。我们还将表征酮对神经递质稳态的影响。我们的数据将完善我们对脑单羧酸代谢的理解，并将对减少脑功能障碍，损伤甚至低血糖死亡的新疗法具有重要意义。也许更重要的是，这种新颖的疗法可能会为1型糖尿病患者的葡萄糖控制更紧密，从而减少严重低血糖症的脑损伤风险，从而降低了脑损伤的风险，从而可以更具侵略性的治疗和减少长期并发症。