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.

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 这种疗法的益处仍然受到频繁而严重的低血糖发作的限制。这些比赛 降低大脑检测后续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 严重的低血糖事件，包括癫痫发作、昏迷和永久性脑损伤等不良后果。 对患有2型糖尿病的老年人的研究发现，低血糖是导致糖尿病的主要危险因素 死亡率、心血管疾病、跌倒甚至痴呆症的增加，突显了其勤奋的必要性 避免和个体化治疗目标。这在长期存在的类风湿关节炎患者中尤其值得关注。 1糖尿病(T1 DM)，通常在更年轻的时候就有几十年的疾病暴露。最近 对老年T1糖尿病患者的研究发现，低血糖、意识不清和血糖变异性是关键的危险因素 对于额外的严重低血糖发作和认知障碍，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。用核磁共振波谱和13C-乙酸酯在啮齿动物模型和 我们发现T1 DM患者大脑能量底物摄取和利用增强是 反复低血糖后大脑代谢的改变和脑内交替燃料水平的增加 损害荷尔蒙的反调节。令人鼓舞的是，研究表明，严格避免低血糖是通过 细致的血糖控制可以恢复荷尔蒙反应和低血糖意识。预测性低 血糖管理(PLGM)系统结合了传感器增强泵疗法的优势和 自动基础胰岛素悬浮液，以减少低血糖暴露。PLGM的表现优于目前可用的 预防低血糖的基础胰岛素悬浮技术。然而，该药的安全性和临床疗效 这种干预以及对老年人反调节的影响还没有确定。因此， 这项提议的目标是在老年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 反调节荷尔蒙反应。我们研究的最终目的是为了证明临床上 技术驱动的方法在老年T1 DM患者中实现严格的血糖控制的有效性 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 已经组建了一支由来自内分泌学、磁学的翻译科学家组成的高度熟练的跨学科团队 磁共振(MR)研究和老年医学是T1 DM脑代谢方面的专家，MR的发展 人工胰腺系统的方法学、临床应用，以及招募、评估和保留 关于老年人的问题。