Regulation of Brain Glucose Metabolism in Type 1 Diabetes

摘要： 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病率 并发症尽管有许多技术的发展，如连续葡萄糖监测仪和封闭式 回路胰岛素泵、低血糖无意识和对低血糖的恐惧仍然是最大的障碍 1型糖尿病（T1 DM）患者的血糖控制。频繁发作的低血糖减少 大脑检测低血糖和激活保护性反调节激素反应的能力 （CRR）。因此，低血糖相关的自主神经功能衰竭（HAAF）伴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，包括认知功能障碍。 损伤癫痫和永久性脑损伤这一问题在T1 DM患者中尤其值得关注， 研究表明，在患者生命早期发生的严重和复发性低血糖可导致认知功能障碍， 损伤和持久的脑损伤。因此，识别驱动反调节失败的机制 和中枢神经系统并发症仍然是一个重要的研究领域， 制定预防战略。以前的范式一直集中在替代能源的贡献 底物如乙酸盐和乳酸盐在复发性低血糖（RH）背景下对脑代谢的影响; 然而，根据最近的观察，它们的作用似乎有限。相反，大脑的调节 血脑屏障（BBB）处的葡萄糖摄取及其线粒体中的神经元氧化已经出现， 在这一领域更主要的监管措施：我们首次在T1 DM中描述了RH暴露限制 通过降低丙酮酸脱氢酶（PDH）活性，神经元葡萄糖利用，从而提供了一个理论基础 以获得更高的乳酸生产率。在最近的一项临床试点研究中，我们发现了一个令人兴奋的现象， 通过小分子激酶抑制剂二氯醋酸盐（DCA）对PDH复合物进行药理学再活化 在强化治疗的T1 DM患者中逆转与复发性低血糖相关的认知缺陷 exposure.根据这项建议，我们将利用新开发的基于NRM的氘代谢 一种允许同时测量大脑所有区域的代谢的成像（EEG）方法， 结合临床前和临床研究确定DCA影响葡萄糖的机制 摄取，氧化代谢和区域乳酸盐的产生，以及这最终如何导致保存大脑 能量、激素反调节和低血糖下的认知功能。最后，这些研究 将产生重要的新信息，以调整我们的治疗方法，以保护大脑免受低血糖的影响， 损伤，最终使糖尿病患者的血糖控制更加严格。

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.