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。尽管有许多技术发展，如连续血糖监测仪和封闭式 循环胰岛素泵、低血糖意识不清和对低血糖的恐惧仍然是最大的障碍 在1型糖尿病(T1 DM)患者中实现严格的血糖控制。频繁发作的低血糖会减少 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，低血糖与自主神经衰竭(HAF)相关，并伴有胰高血糖素和肾上腺素的减少 释放会增加发生更严重低血糖事件的风险，并带来包括认知在内的不良后果 损伤、癫痫发作和永久性脑损伤。这个问题在T1 DM中尤其令人担忧，因为最近 研究表明，在患者生命早期发生的严重和反复的低血糖会导致认知 损伤和持久的脑损伤。因此，确定了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 制定预防策略。以前的范例都集中在替代能源的贡献上。 在反复低血糖(RH)的背景下，醋酸盐和乳酸等底物对大脑代谢的影响； 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)的葡萄糖摄取及其在线粒体中的神经元氧化表现为 这一领域更主要的监管步骤：我们首次在T1 DM中描述了RH暴露是如何限制的 通过降低丙酮酸脱氢酶(PDH)活性来利用神经元葡萄糖，从而提供了一个理论基础 更高的乳酸盐产生率。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发现 小分子激酶抑制剂二氯乙酸酯(DCA)对PDH复合体的药理作用 强化治疗的T1 DM患者可逆转与复发性低血糖相关的认知障碍 曝光。根据这项提议，我们将利用新开发的基于NRM的重氢代谢 成像(DMI)方法，允许同时测量大脑所有区域的新陈代谢 结合临床前和临床研究确定DCA影响血糖的机制 摄取、氧化代谢和局部乳酸产生及其最终如何导致大脑保存 低血糖下的能量学、荷尔蒙反调节和认知功能。最后，这些研究 将产生重要的新信息来定制我们保护大脑免受低血糖影响的治疗方法 伤害，最终使糖尿病患者能够更严格地控制血糖。

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.