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: 9280934
• 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
• 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/9280934
• 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; Homeostasis; Human; Hypoglycemia; Impaired cognition; In Vitro; Incidence; Individual; Infusion procedures; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Isotope Labeling; Knowledge; Label; Life; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; NMR Spectroscopy; Neurons; Neurotransmitters; PDH kinase; Patients; Peripheral; Pharmacology; 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; public health relevance; pyruvate dehydrogenase; restoration; therapy development; type I diabetic; uptake

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使血糖水平正常化，降低糖尿病并发症的发生率。然而，这种治疗方案的益处仍然受到频繁和严重的低血糖发作的限制。这些事件降低了大脑检测低血糖和激活反调节防御的能力，进一步增加了随后发生低血糖的风险。因此，低血糖症可能在没有警告症状或睡眠期间发生，这强调了预防策略的必要性，并最大限度地减少其潜在的不良后果，如癫痫发作，昏迷和永久性损伤。这一问题在1型糖尿病（T1 DM）中尤其值得关注，最近的研究表明，患者生命早期发生的严重和复发性低血糖可导致认知障碍和持久的脑损伤。之前我们发现，在T1 DM和复发性低血糖大鼠模型中，单羧酸乙酸酯的转运和代谢上调，表明替代燃料消耗增加在低血糖无意识中起主要作用。然而，当我们研究更相关的替代燃料乳酸盐时，我们惊讶地发现，增强的乳酸盐运输并没有与乳酸盐利用率的增加齐头并进，而是刺激了大脑的葡萄糖代谢。我们在啮齿类动物中的观察结果已被最近在T1 DM受试者中进行的一项研究证实。这些发现支持乳酸盐在T1 DM低血糖期间具有双重作用的概念，即作为葡萄糖代谢的底物和激活剂。我们最近获得了额外的了解，通过其对神经元丙酮酸脱氢酶（PDH）复合物活性的影响，这种乳酸悖论。我们的初步结果表明，PDH在低血糖时受到抑制，这种抑制作用可以被血浆乳酸逆转。如果该模型是正确的，T1 DM中葡萄糖代谢的保留（可能在低血糖无意识中起重要作用）是由于转运升高，脑乳酸水平升高和防止PDH抑制。因此，本提案的总体目标是确定复发性低血糖背景下脑乳酸和葡萄糖代谢的相互作用，以建立T1 DM患者维持脑代谢（和功能）并意识到低血糖的分子机制。我们将使用核磁共振波谱来确定13 C标记的葡萄糖和乳酸在反复低血糖的情况下对脑代谢的贡献。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。将在低血糖无意识的T1 DM患者和使用13 C-葡萄糖和乳酸盐的匹配对照中，通过NMR光谱测试这些结果的人体相关性。