Regulation of Brain Glucose Metabolism in Type 1 Diabetes

1 型糖尿病脑葡萄糖代谢的调节

基本信息

批准号：
10379262
负责人：
Raimund Ingo Herzog
金额：
$ 48.54万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379262
关键词：
Acetates Address Affect Area Automobile Driving Blood - brain barrier anatomy Blood Circulation Blood Glucose Brain Brain Injuries Cell Respiration Clinical Clinical Research Closure by clamp Cognition Cognitive deficits Complications of Diabetes Mellitus Deuterium Development Diabetes Mellitus Dichloroacetate Dose Epinephrine Event Exposure to Failure Fright Future Glucagon Glucose Hormonal Hormones Hypoglycemia Hypothalamic structure Impaired cognition Impairment Incidence Injury Insulin Insulin Infusion Systems Insulin-Dependent Diabetes Mellitus Label Lead Life Memory Metabolic Methods Mitochondria Modeling Neuraxis Neurocognitive Neurons Oral Oxidation-Reduction Patients Peripheral Pharmacology Phosphotransferases Pilot Projects Prevention strategy Production Protein Isoforms Pyruvate Dehydrogenase Complex Rattus Reaction Time Recurrence Regulation Risk Role Seizures Site Therapeutic Time Tracer adverse outcome base blood glucose regulation brain metabolism cognitive function cognitive testing counterregulation diabetic patient falls follow-up functional disability glucose metabolism glucose monitor glucose uptake glycemic control hypoglycemia unawareness imaging modality improved insight kinase inhibitor metabolic imaging metabolomics novel oxidation preclinical study preservation pyruvate dehydrogenase response restoration small molecule type I diabetic

项目摘要

Abstract: Normalization of blood glucose levels via intensive insulin therapy reduces the incidence of diabetic complications. Despite numerous technologic developments such as continuous glucose monitors and closed loop insulin pumps, hypoglycemia unawareness and fear of hypoglycemia remain among the biggest obstacles to achieving tight glycemic control in type 1 diabetic (T1DM) patients. Frequent bouts of hypoglycemia diminish the brain’s capacity to detect hypoglycemia and to activate protective counterregulatory hormonal responses (CRR). As a result hypoglycemia associated autonomic failure (HAAF) with reduced glucagon and epinephrine release increases the risk of more severe hypoglycemic events with adverse consequences including cognitive impairment, seizures and permanent brain injury. This issue is of particular concern in 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. Thus identification of the mechanisms driving counterregulatory failure and central nervous system complications remain an important area of study with the hope of ultimately devising preventive strategies. Previous paradigms have been focused on the contribution of alternate energy substrates such as acetate and lactate to brain metabolism in the context of recurrent hypoglycemia (RH); however in the light of more recent observations, their role appears only limited. Instead, the regulation of brain glucose uptake at the blood brain barrier (BBB) and its neuronal oxidation in mitochondria have emerged as more dominant regulatory steps in this area: We describe for the first time in T1DM how RH exposure limits neuronal glucose utilization by reducing pyruvate dehydrogenase (PDH) activity, thereby providing a rationale for higher lactate production rates. In a recent clinical pilot study we made the exciting observation that pharmacologic re-activation of the PDH complex via the small molecule kinase inhibitor dichloroacetate (DCA) in intensively treated T1DM patients reverses cognitive deficits associated with recurrent hypoglycemia exposure. Under this proposal we will take advantage of a newly developed NRM-based deuterium metabolic imaging (DMI) method that permits metabolism measurements across all areas of the brain simultaneously to determine in a combination of preclinical and clinical studies the mechanism by which DCA affects glucose uptake, oxidative metabolism and regional lactate production and how this ultimately leads to preserved brain energetics, hormonal counterregulation and cognitive function under hypoglycemia. In the end these studies will yield important new information to tailor our therapeutic approaches to protect the brain from hypoglycemic injury, ultimately permitting tighter glycemic control in diabetes.

抽象的：通过强化胰岛素治疗使血糖水平正常化可降低糖尿病的发生率尽管有许多技术发展，例如连续血糖监测仪和封闭式血糖仪。循环胰岛素泵、低血糖意识和对低血糖的恐惧仍然是最大的障碍 1 型糖尿病 (T1DM) 患者的频繁低血糖发作得到严格控制。大脑检测低血糖和激活保护性反调节激素反应的能力 (CRR) 结果导致低血糖相关自主神经衰竭 (HAAF) 与胰高血糖素和肾上腺素减少。释放会增加更严重的低血糖事件的风险，并产生不良后果，包括认知障碍损伤、癫痫发作和永久性脑损伤这一问题在 T1DM 中尤其令人关注。研究表明，患者生命早期发生的严重且反复发生的低血糖可能会导致认知障碍从而确定导致反监管失败的机制。中枢神经系统并发症仍然是一个重要的研究领域，希望最终能够制定预防策略的范例一直集中在替代能源的贡献上。复发性低血糖 (RH) 情况下，醋酸盐和乳酸等底物对脑代谢的影响；然而，根据最近的观察，它们的作用似乎很有限，相反，它们对大脑的调节作用似乎有限。血脑屏障（BBB）的葡萄糖摄取及其在线粒体中的神经元氧化已出现该领域更具主导性的监管措施：我们首次在 T1DM 中描述如何限制 RH 暴露通过降低丙酮酸脱氢酶（PDH）活性来利用神经元葡萄糖，从而提供了一个基本原理在最近的一项临床试点研究中，我们做出了令人兴奋的观察：通过小分子激酶抑制剂二氯乙酸酯 (DCA) 药理学重新激活 PDH 复合物在接受强化治疗的 T1DM 患者中，可逆转与反复低血糖相关的认知缺陷根据该提案，我们将利用新开发的基于 NRM 的氘代谢。成像（DMI）方法，允许同时测量大脑所有区域的代谢结合临床前和临床研究确定 DCA 影响葡萄糖的机制摄取、氧化代谢和局部乳酸生成以及这最终如何导致大脑保存最后，这些研究涉及低血糖下的能量学、激素反调节和认知功能。将产生重要的新信息来定制我们的治疗方法以保护大脑免受低血糖的影响损伤，最终可以更严格地控制糖尿病的血糖。