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

使用预测性低血糖管理 (PLGM) 系统逆转患有 1 型糖尿病的老年人的大脑代谢适应，以应对复发性低血糖

• 批准号: 9236876
• 负责人: Raimund Ingo Herzog
• 金额: $ 192.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236876
• 关键词: Acetates; Address; Affect; Age; Algorithms; Artificial Pancreas; Awareness; Blood - brain barrier anatomy; Blood Glucose; Brain; Brain Injuries; Carbon; Cardiovascular Diseases; Clinical; Cognition; Cognitive; Coma; Complications of Diabetes Mellitus; Data; Dementia; Development; Disease; Elderly; Endocrinology; Epinephrine; Event; Frequencies; Geriatrics; Glucagon; Glucose; Goals; Hormonal; Hormones; Hypoglycemia; Impaired cognition; Impairment; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Magnetic Resonance; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Patients; Performance; Plasma; Prevention; Prevention strategy; Psychomotor Performance; Pump; Questionnaires; Recurrence; Regimen; Research; Risk; Risk Factors; Rodent Model; Safety; Scientist; Seizures; Severities; Surveys; Suspension substance; Suspensions; Symptoms; System; Technology; Time; Work; abstracting; adverse outcome; basal insulin; base; blood glucose regulation; brain metabolism; clinical efficacy; cognitive function; cognitive testing; counterregulation; falls; frontal lobe; glycemic control; hypoglycemia unawareness; improved; individualized medicine; intervention effect; mortality; novel; oxidation; response; satisfaction; sensor; uptake

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.

抽象的： 通过强化胰岛素治疗使血糖正常化可以降低糖尿病并发症的发生率，但是 这种治疗方案的益处仍然受到频繁且严重的低血糖发作的限制。这些回合 降低大脑检测随后的低血糖和激活保护性反调节的能力 荷尔蒙反应，胰高血糖素和肾上腺素释放减少，从而增加更多风险 严重的低血糖事件会带来不良后果，包括癫痫、昏迷和永久性脑损伤。 针对患有 2 型糖尿病的老年人的研究表明，低血糖是导致 2 型糖尿病的主要危险因素。 死亡率、心血管疾病、跌倒甚至痴呆症增加，凸显了其勤奋的必要性 回避和个体化治疗目标。对于长期患有此类疾病的患者来说，这一点尤其值得关注。 1 型糖尿病 (T1DM)，他们通常在年轻时就已患病数十年。最近的一个 对老年 T1DM 患者的研究发现，低血糖意识和血糖变异性是关键危险因素 对于额外的严重低血糖发作和认知受损，进一步强调了未得到满足的需求 全面定义大脑对低血糖的适应，并确定改善的预防策略 血糖控制。在啮齿动物模型和 我们发现 T1DM 患者的大脑能量底物摄取和利用增强是 反复低血糖后大脑代谢发生改变，大脑中的替代燃料水平增加 损害荷尔蒙反调节。令人鼓舞的是，研究表明，通过严格避免低血糖 细致的血糖控制可以恢复荷尔蒙反应和低血糖意识。预测低位 血糖管理 (PLGM) 系统结合了传感器增强泵疗法的优点 自动基础胰岛素悬浮液可减少低血糖暴露。 PLGM 的性能优于现有产品 用于预防低血糖的基础胰岛素悬浮技术。然而，其安全性和临床疗效 这种干预措施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 T1DM 患者中实施 PLGM 系统，以逆转大脑 代谢适应并恢复代谢敏感性、低血糖意识和适当的 反调节荷尔蒙反应。我们研究的最终目的是证明临床 技术驱动的方法对患有 T1DM 的老年人实现严格血糖控制的有效性，无需 让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 组建了一支高技能的跨学科团队，由来自内分泌学、磁学等领域的转化科学家组成 共振 (MR) 研究和老年病学专家，T1DM 脑代谢、MR 的发展 人工胰腺系统的方法、临床实施以及招募、评估和保留 的老年人。