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：
9897264
负责人：
Raimund Ingo Herzog
金额：
$ 50.25万
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/9897264
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的血糖水平归一化可降低糖尿病的发生率并发症。尽管有许多技术发展，例如连续葡萄糖监测器和关闭循环胰岛素泵，低血糖不认识和对低血糖的恐惧仍然是最大的障碍为了在1型糖尿病（T1DM）患者中获得严格的血糖控制。低血糖的经常发作大脑检测低血糖和激活保护性反调节激素反应的能力（CRR）。结果低血糖相关的自主衰竭（HAAF）与胰高血糖素和肾上腺素还原释放增加了更严重的降血糖事件的风险，以及不良后果包括认知损伤，癫痫发作和永久性脑损伤。这个问题在T1DM中特别关注研究表明，严重和复发性低血糖症发生在患者的生活早期可能导致认知损害和持久的脑损伤。鉴定驱动反调节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，希望最终制定预防策略。以前的范式一直集中在替代能量的贡献上在复发性低血糖症（RH）的背景下，乙酸和脑代谢等底物；但是，鉴于最近的观察结果，它们的作用只是有限的。相反，大脑的调节血液脑屏障（BBB）及其在线粒体中的神经元氧化的吸收已出现该领域的更主导的监管步骤：我们在T1DM中首次描述RH暴露限制如何通过减少丙酮酸脱氢酶（PDH）活性，神经元葡萄糖利用，从而提供了基本原理对于更高的乳酸生产率。在最近的一项临床试点研究中，我们进行了令人兴奋的观察结果 PDH复合物通过小分子激酶抑制剂二氯乙酸（DCA）重新激活PDH复合物（DCA）在经过大量治疗的T1DM患者中，认知定义与复发性低血糖相关接触。根据该建议，我们将利用新开发的基于NRM的氘代谢成像（DMI）方法，允许大脑所有区域的新陈代谢测量在临床前和临床研究的结合中确定DCA影响葡萄糖的机制摄取，氧化代谢和区域裂缝的产生以及这最终如何导致大脑低血糖症下的能量，骑马的反调节和认知功能。最后这些研究将产生重要的新信息，以量身定制我们的治疗方法，以保护大脑免受降血糖的侵害损伤，最终允许糖尿病中的血糖控制更严格。