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。

• 批准号: 8622673
• 负责人: Raimund Ingo Herzog
• 金额: $ 8.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/8622673
• 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; 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; public health relevance; pyruvate dehydrogenase; response; type I diabetic; uptake

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)：糖尿病并发症可以通过强化胰岛素治疗使血糖水平正常化来减少。这种治疗虽然有效，但有增加复发性低血糖发生率的风险。它削弱了中枢对低血糖的反调节反应(反调节失败)，从而放大了严重低血糖和脑损伤的风险。这项建议旨在描述1型糖尿病强化胰岛素治疗的中枢神经系统并发症；具体地说， 大脑代谢异常及其对反复低血糖的适应性，这是低血糖意识不清的主要原因。我们小组先前来自1型糖尿病患者的数据显示，低血糖下大脑利用替代燃料的能力增强，这可能是由于转运蛋白表达增加所致。我们的反复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，注入的单羧酸，如醋酸盐和乳酸，可以作为葡萄糖以外的能量底物，并在低血糖下支持大脑代谢。先证性复发性低血糖通过增加替代燃料进入大脑的功能来增强这些效应。在测试乳酸作为替代燃料时，我们做出了令人惊讶的观察，即使在反复低血糖后乳酸盐的摄取有所增强，但它仍然对整体大脑氧化能力没有显著贡献。综上所述，我们提出假设，如果一种候选燃料不会受到与乳酸相同的限制，那么反复低血糖会增强大脑对单元酸的吸收，这可以被用来支持神经元新陈代谢。因为它不依赖于丙酮酸脱氢酶转化的潜在限制步骤，所以β-羟基丁酸酯就是这样的燃料之一。因此，我们建议确定神经元燃料β-羟丁酸在低血糖条件下支持新陈代谢和维持人脑能量平衡的能力。在交叉研究设计中，我们将在欧洲和低血糖钳夹研究期间，通过碳-13核磁共振波谱表征健康对照组和1型糖尿病受试者的脑酮代谢。当葡萄糖供应有限时，通过提供替代燃料，我们将能够确定酮对整体大脑新陈代谢的贡献。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，并将对创造新的治疗方法以减少脑功能障碍、损伤甚至低血糖导致的死亡具有重要意义。也许更重要的是，这种新的疗法可能提供机会，实现对1型糖尿病患者更严格的血糖控制，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和减少长期并发症。