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）：糖尿病并发症可通过强化胰岛素治疗使血糖水平正常化而减少。这种治疗虽然有效，但有增加复发性低血糖发生率的风险。它削弱了对低血糖的中枢反调节反应（反调节失败），从而增加了严重低血糖和脑损伤的风险。本研究旨在描述1型糖尿病患者强化胰岛素治疗后的中枢神经系统并发症；具体地说,