Reversing brain metabolic adaptations to recurrent hypoglycemia in older adults with type 1 diabetes using a Predictive Low Glucose Management (PLGM) system

摘要： 通过强化胰岛素治疗使血糖正常化可降低糖尿病并发症的发生率，但 这些方案的益处仍然受到频繁和严重的低血糖发作的限制。这些回合 降低大脑检测后续低血糖和激活保护性反调节的能力 激素反应，胰高血糖素和肾上腺素释放减少，从而增加更多的风险 严重低血糖事件，不良后果包括癫痫发作、昏迷和永久性脑损伤。 在老年2型糖尿病患者中进行的研究已经确定低血糖是导致糖尿病的主要危险因素。 增加死亡率，心血管疾病，福尔斯，甚至痴呆症，突出了其勤奋的必要性 避免和个性化治疗目标。这是特别关注的患者长期型 1型糖尿病（T1 DM）患者通常在更年轻的时候就有几十年的疾病暴露。最近的一 一项老年T1 DM患者的研究发现，低血糖无意识和血糖变异性是关键风险因素 对于额外的严重低血糖发作和认知受损，进一步强调了未满足的需求， 全面定义大脑对低血糖的适应，并确定预防策略， 血糖控制。使用磁共振光谱和碳-13醋酸盐在啮齿动物模型和 我们发现T1 DM患者脑能量底物摄取和利用增强是T1 DM的标志， 在反复低血糖后改变脑代谢，并增加大脑中的替代燃料水平 削弱荷尔蒙反调节。令人鼓舞的是，它表明，严格避免低血糖，通过 细致的血糖控制可以恢复激素反应和低血糖意识。预测低 葡萄糖管理（PLGM）系统联合收割机将传感器增强泵治疗的优点与 自动基础胰岛素暂停，以减少低血糖暴露。PLGM性能优于当前可用产品 预防低血糖的基础胰岛素悬液技术。然而，安全性和临床疗效 这种干预以及对老年人反调节的影响尚未确定。因此 该提案的目标是在老年T1 DM患者中实施PLGM系统，以逆转大脑 代谢适应和恢复代谢敏感性，低血糖意识和适当的 反调节激素反应。我们研究的最终目的是证明临床 技术驱动的方法在老年T1 DM患者中实现严格血糖控制而不 使这些特别脆弱的患者面临严重低血糖的风险。为了实现这一目标，我们 组建了一支由内分泌学、磁学、生物医学和生物医学领域的翻译科学家组成的高技能跨学科团队， 共振（MR）研究和老年医学专家，他们是T1 DM脑代谢、MR发展 方法学、人工胰腺系统的临床实施以及招募、评估和保留 老年人。

Abstract: Normalizing plasma glucose via intensive insulin therapy reduces the incidence of diabetic complications, but the benefits of such regimens remain limited by frequent and severe bouts of hypoglycemia. These bouts diminish the brain's capacity to detect subsequent hypoglycemia and to activate protective counterregulatory hormonal responses, with reduced glucagon and epinephrine release, thereby increasing the risk of more severe hypoglycemic events with adverse consequences including seizures, coma and permanent brain injury. Studies in older adults with type 2 diabetes have identified hypoglycemia as the major risk factor contributing to increased mortality, cardiovascular disease, falls and even dementia, highlighting the need for its diligent avoidance and individualized treatment targets. This is of particular concern in patients with longstanding type 1 diabetes (T1DM) who often have had several decades of disease exposure at a much younger age. A recent study of elderly T1DM patients found hypoglycemia unawareness and glycemic variability to be key risk factors for additional severe hypoglycemic episodes and impaired cognition, further underscoring the unmet need to comprehensively define brain adaptations to hypoglycemia and to identify preventative strategies that improve glycemic control. Using magnetic resonance spectroscopy and carbon-13 acetate both in rodent models and T1DM patients we found that enhanced brain energy substrate uptake and utilization are the hallmarks of altered brain metabolism after recurrent hypoglycemia and that increased alternate fuel levels in the brain impair hormonal counterregulation. Encouragingly, it was shown that strict avoidance of hypoglycemia via meticulous glucose control can restore hormonal responses and hypoglycemia awareness. Predictive low glucose management (PLGM) systems combine the advantages of sensor augmented pump therapy with automated basal insulin suspension to reduce hypoglycemia exposure. PLGM outperforms currently available basal insulin suspension technology for hypoglycemia prevention. However, the safety and clinical efficacy of this intervention, and the effect on counterregulation in older adults, have not been defined. Therefore the goals of this proposal are to implement a PLGM system in older T1DM patients in order to reverse brain metabolic adaptations and restore metabolic sensitivity, hypoglycemia awareness and appropriate counterregulatory hormonal responses. The ultimate purpose of our studies is to demonstrate the clinical usefulness of a technology-driven approach in older adults with T1DM to achieve tight glycemic control without exposing these particularly vulnerable patients to the risks of profound hypoglycemia. To approach this aim we have assembled a highly skilled interdisciplinary team of translational scientists from endocrinology, magnetic resonance (MR) research and geriatrics who are experts in brain metabolism in T1DM, development of MR methodology, clinical implementation of artificial pancreas systems, and recruitment, assessment and retention of older persons.