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

基本信息

批准号：
9097688
负责人：
Raimund Ingo Herzog
金额：
$ 37.46万
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：
2014-09-24 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097688
关键词：
Acetates Acids Address Animal Model Astrocytes Blood Glucose Brain Brain Injuries Citric Acid Cycle Coma Complications of Diabetes Mellitus Consumption Coupling Data Diabetes Mellitus Exposure to Glucose Goals Health Homeostasis Human Hypoglycemia Impaired cognition In Vitro Incidence Infusion procedures Injury Insulin Insulin-Dependent Diabetes Mellitus Investigation Knowledge Label Life Metabolic Metabolism Mitochondria Modeling Molecular Molecular Target NMR Spectroscopy Neurons Neurotransmitters PDH kinase Patients Peripheral Phosphotransferases Plasma Play Predisposition Prevention strategy Pyruvate Pyruvate Dehydrogenase Complex Rattus Recurrence Regimen Regulation Risk Rodent Rodent Model Role Seizures Sleep Small Interfering RNA Streptozocin Symptoms Testing Therapeutic Tracer Treatment Protocols adverse outcome base blood glucose regulation brain metabolism defined contribution diabetic diabetic patient glucose metabolism glycemic control hypoglycemia unawareness in vivo insight knock-down novel therapeutic intervention prevent pyruvate dehydrogenase restoration therapy development type I diabetic uptake

项目摘要

DESCRIPTION (provided by applicant): Normalization of blood glucose levels via intensive insulin therapy reduces the incidence of diabetic complications. However, the benefits of such treatment regimens remain limited by frequent and severe bouts of hypoglycemia. These episodes diminish the brain's capacity to detect hypoglycemia and to activate counterregulatory defenses, further increasing the risk of subsequent hypoglycemia. As a result, hypoglycemia can occur without warning symptoms or during sleep, underscoring the need for preventive strategies and of minimizing its potential adverse consequences like seizures, coma and permanent injury. This issue is of particular concern in type 1 diabetes (T1DM) where recent studies suggest that severe and recurrent hypoglycemia occurring early in a patient's life can result in cognitive impairment and lasting brain damage. Previously we found that transport and metabolism of the monocarboxylic acid acetate was upregulated in T1DM and in a recurrent hypoglycemia rat model indicating that enhanced alternate fuel consumption plays a major role in hypoglycemia unawareness. However, when we studied the more relevant alternate fuel lactate, we found to our surprise that enhanced lactate transport did not go hand in hand with increased lactate utilization, but stimulated brain glucose metabolism instead. Our observations in rodents have since been confirmed by a recent study in T1DM subjects. These findings support the concept of lactate having a dual role during hypoglycemia in T1DM, as both a substrate and as an activator of glucose metabolism. We have recently gained additional insight into this lactate paradox through its impact on neuronal pyruvate dehydrogenase (PDH) complex activity. Our preliminary results suggest that PDH is inhibited during hypoglycemia, and that this inhibition can be reversed by plasma lactate. If this model is correct the preserved glucose metabolism in T1DM, which may play an important role in hypoglycemia unawareness, is due to elevated transport raising brain lactate levels and preventing inhibition of PDH. Thus, the overall goal of this proposal is to define the interplay of brain lactate and glucose metabolism in the context of recurrent hypoglycemia to establish the molecular mechanism by which T1DM patients sustain brain metabolism (and function) and become unaware of hypoglycemia. We are going to use NMR spectroscopy to define the contributions of 13C-labeled glucose and lactate to brain metabolism in the setting of recurrent hypoglycemia. In addition we will use pharmacologic and siRNA knockdown approaches to determine the role of PDH inhibiting kinases in the suppression of PDH flux under hypoglycemia. The human relevance of these findings will be tested by NMR spectroscopy in T1DM patients with hypoglycemia unawareness and matched controls using 13C-glucose and lactate.

描述（由申请人提供）：通过强化胰岛素治疗的血糖水平归一化可降低糖尿病并发症的发生率。但是，这种治疗方案的益处仍然受到频繁和严重的低血糖症的限制。这些发作降低了大脑检测低血糖和激活反调节性防御的能力，从而进一步增加了随后的低血糖的风险。结果，低血糖可以在没有警告症状或睡眠期间发生，强调需要进行预防策略，并最大程度地减少其潜在的不良后果，例如癫痫发作，昏迷和永久性伤害。该问题在1型糖尿病（T1DM）中特别关注，最近的研究表明，患者生命的早期发生严重和复发性低血糖会导致认知障碍和持久的脑损伤。以前，我们发现在T1DM和复发性低血糖大鼠模型中，单核酸乙酸单羧酸的转运和代谢被上调，这表明增强的替代燃料消耗在低血糖不认识中起主要作用。但是，当我们研究了更相关的替代燃料乳酸时，我们惊讶地发现，增强的乳酸转运并未与增加的乳酸利用率齐头并进，而是刺激了脑葡萄糖代谢。此后，最近在T1DM受试者中进行了一项研究证实了我们对啮齿动物的观察结果。这些发现支持乳酸在T1DM中低血糖症中具有双重作用的概念，既是底物，又是葡萄糖代谢的激活剂。最近，我们通过对神经丙酮酸脱氢酶（PDH）复合活性的影响，对这种乳酸悖论获得了更多的了解。我们的初步结果表明，在低血糖期间，PDH受到抑制，并且这种抑制作用可以被血浆乳酸逆转。如果该模型是正确的，那么T1DM中保留的葡萄糖代谢可能在低血糖中起重要作用，这是由于升高的转运增加了脑乳酸水平并防止PDH抑制。因此，该提案的总体目标是在复发性低血糖症的背景下定义脑乳酸和葡萄糖代谢的相互作用，以建立T1DM患者维持脑代谢（和功能）并不知道低血糖症的分子机制。我们将使用NMR光谱法来定义13C标记的葡萄糖和乳酸对脑代谢的贡献。此外，我们将使用药理学和siRNA敲低方法来确定PDH抑制激酶在低血糖下抑制PDH通量中的作用。这些发现的人类相关性将通过NMR光谱法对低血糖不认识的T1DM患者进行测试，并使用13C-葡萄糖和乳酸盐进行了匹配的对照。