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:8622673
- 负责人:
- 金额:$ 8.32万
- 依托单位:
- 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:
- 关键词:AcetatesAcidsAcuteAddressAgeAnimal ModelBlood - brain barrier anatomyBlood GlucoseBlood specimenBrainBrain InjuriesButyratesCarbonCarrier ProteinsCatecholaminesCessation of lifeChildCitric Acid CycleComplications of Diabetes MellitusCross-Over StudiesDataDevelopmentDiabetes MellitusEnergy MetabolismExposure toFailureFastingFunctional disorderGlucagonGlucoseGlutamatesGoalsHomeostasisHormonalHumanHydroxybutyratesHypoglycemiaImpaired cognitionImpairmentIn Vivo NMR SpectroscopyIncidenceIndividualInfusion proceduresInjuryInsulinInsulin-Dependent Diabetes MellitusIsotope LabelingKetone BodiesKetonesLifeMagnetic Resonance SpectroscopyMeasurementMeasuresMetabolicMetabolismNMR SpectroscopyNeuronsNeurotransmittersOutcomePatientsPositioning AttributePrevention strategyProductionProtonsRecurrenceResearch DesignRiskRodent ModelRoleSleepSymptomsTestingTreatment ProtocolsUrsidae Familyadverse outcomebasebeta-Hydroxybutyrateblood glucose regulationbrain metabolismcognitive functiondiabeticdiabetic patientexperiencegamma-Aminobutyric Acidglycemic controlhealthy volunteerhuman subjecthypoglycemia unawarenessimprovedin vivonovelnovel therapeutic interventionprotein expressionpublic health relevancepyruvate dehydrogenaseresponsetype I diabeticuptake
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减少糖尿病并发症。这种治疗虽然有效,但有增加复发性低血糖发生率的风险。它减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。该提案旨在描述1型糖尿病强化胰岛素治疗的CNS并发症;具体而言,
脑代谢异常及其对复发性低血糖的适应,这是低血糖无意识的主要原因。来自我们1型糖尿病患者组的先前数据显示,在低血糖情况下,大脑利用替代燃料的能力增加,这可能是由于转运蛋白表达增加。来自我们的复发性低血糖动物模型的初步体内NMR光谱数据证实了这些发现,因为我们发现输注的单羧酸如乙酸盐和乳酸盐可以作为葡萄糖以外的能量底物,并在低血糖下支持脑代谢。先前复发性低血糖通过功能性增加进入大脑的替代燃料运输来增强这些作用。当测试乳酸作为替代燃料时,我们发现了一个令人惊讶的观察结果,即即使在暴露于复发性低血糖后其摄取增加,但它仍然对整体脑氧化能力没有显着贡献。总之,这使我们假设,复发性低血糖会增强脑中一元羧酸的摄取,如果候选燃料不会受到与乳酸相同的限制,则可以利用一元羧酸来支持神经元代谢。因为它不依赖于丙酮酸脱氢酶转化的潜在限制步骤,β-羟基丁酸酯就是这样一种燃料。因此,我们建议确定神经元燃料β-羟基丁酸盐在低血糖下支持代谢通量和支持人脑能量稳态的能力。在交叉研究设计中,我们将在eu-和低血糖钳夹研究期间通过碳-13 NMR光谱表征健康对照和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个大脑代谢的贡献。我们还将描述酮对神经递质稳态的影响。我们的数据将完善我们对大脑单羧酸代谢的理解,并将对创造新疗法以减少低血糖引起的大脑功能障碍、损伤甚至死亡产生重要影响。也许更重要的是,这种新的治疗方法可以提供机会,实现1型糖尿病患者的更严格的血糖控制,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。
项目成果
期刊论文数量(0)
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Raimund Ingo Herzog其他文献
Ein Polymorphismus im Intron 3 des p53-Gens und erhöhtes Risiko für Ovarialkarzinom
- DOI:
10.18725/oparu-108 - 发表时间:
2000-05 - 期刊:
- 影响因子:0
- 作者:
Raimund Ingo Herzog - 通讯作者:
Raimund Ingo Herzog
Raimund Ingo Herzog的其他文献
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Mechanism of ultrasound neuromodulation effects on glucose homeostasis and diabetes
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- 批准号:
10586211 - 财政年份:2023
- 资助金额:
$ 8.32万 - 项目类别:
Reversing brain metabolic adaptations to recurrent hypoglycemia in older adults with type 1 diabetes using a Predictive Low Glucose Management (PLGM) system
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9236876 - 财政年份:2016
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$ 8.32万 - 项目类别:
Regulation of Brain Glucose Metabolism in Type 1 Diabetes
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10379262 - 财政年份:2014
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$ 8.32万 - 项目类别:
Regulation of Brain Glucose Metabolism by Alternate Fuels in Type 1 Diabetes
1 型糖尿病中替代燃料对脑葡萄糖代谢的调节
- 批准号:
8818284 - 财政年份:2014
- 资助金额:
$ 8.32万 - 项目类别:
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:
8779720 - 财政年份:2014
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