Advanced Insulin Delivery to Reduce Impaired Awareness of Hypoglycemia in a T1D Cohort (AIDRIAHT1C)

项目概要/摘要 强化胰岛素治疗可降低1型糖尿病微血管和大血管并发症的风险 (T1D)但与严重低血糖的较高风险相关，限制了最佳血糖控制。随着时间的推移， 20-30%的T1 D患者出现低血糖意识受损（IAH），最有可能是由于 低血糖反复和严重发作的后果。IAH本身就是一个重要的风险因素， 随后发生严重的低血糖，导致恶性循环，具有潜在的致命后果。 IAH与对低血糖的反调节反应（CRR）减少和脑内 结构和功能。采用先进技术降低低血糖发生频率（持续 血糖监测[CGM]和胰岛素泵）和有针对性的教育改善了IAH，但并不完全。 提前胰岛素输注降低1型糖尿病患者低血糖意识障碍的研究 （AIDRIAHT 1C）试验旨在测试HCL与传感器增强泵（SAP）治疗相比的疗效， 通过减少低血糖花费的时间，提高对低血糖和CRR的认识。的 本研究将招募不同的T1 D成人人群，病程至少为10年。参与者将被 使用HYPO评分将其归类为患有IAH。IAH患者将以1：1的比例随机分配至两组 两组都将接受旨在减少低血糖的有针对性的教育计划。 在基线和6个月间隔2年，受试者将接受逐步高胰岛素血症- 低血糖钳在12个月时评估的主要结局包括以下共同主要终点： 低血糖的CRR（内源性葡萄糖生成、胰多肽和肾上腺素，检测 分级）和症状识别（自主症状评分，HYPO评分，也分级测试） (Aim 1）。与IAH和低血糖意识恢复相关的因素将根据以下因素确定： 筛选人群和试验参与者（目标2）。一个匹配的对照组健康的非- 将招募糖尿病对照和T1 D受试者以及低血糖意识正常的受试者， 提供基线时对低血糖的正常反应。该研究还旨在开发新的方法 通过测试自我报告项目，CGM提示报告和生理检查的组合来诊断IAH。 使用机器学习和人工智能监测和预测对干预的反应（目标3） 以及研究与IAH改善相关并预测IAH改善的大脑结构和功能（目标4）， 功能磁共振成像，有和没有低血糖。 该研究的最终目标是确定IAH的最佳治疗方法， 有风险的个人，了解IAH的机制，并最终减少相关的负担和风险 严重低血糖，提高T1 D患者的生活质量和治疗满意度。

Project Summary/Abstract Intensive insulin treatment decreases the risk of micro- and macrovascular complications in type 1 diabetes (T1D) but is associated with a higher risk of severe hypoglycemia, limiting optimal glycemic control. Over time, 20-30% of patients with T1D develop impaired awareness of hypoglycemia (IAH), most likely as a consequence of repeated and severe episodes of hypoglycemia. IAH is, itself, a significant risk factor for subsequent episodes of severe hypoglycemia, leading to a vicious cycle with potentially lethal consequences. IAH is associated with diminished counter-regulatory responses (CRR) to hypoglycemia and changes in brain structure and function. Reducing the frequency of hypoglycemia with advanced technologies (continuous glucose monitoring [CGM] and insulin pumps) and targeted education improves IAH, but not completely. The Advanced Insulin Delivery to Reduce Impaired Awareness of Hypoglycemia in a Type 1 Diabetes Cohort (AIDRIAHT1C) trial aims at testing the efficacy of HCL compared to sensor-augmented pump (SAP) therapy to improve awareness of hypoglycemia and CRR by reducing the amount of time spent in hypoglycemia. The study will enroll a diverse population of adults with T1D of at least ten years duration. Participants will be classified as having IAH using the HYPO score. Individuals with IAH will be randomized 1:1 to the two interventions and both groups will receive a targeted educational program designed to decrease hypoglycemia. At baseline and at 6-month intervals for 2 years, participants will undergo step-wise hyperinsulinemic- hypoglycemic clamps. The primary outcome, assessed at 12 months, consists of the co-primary endpoints of CRR to hypoglycemia (endogenous glucose production, pancreatic polypeptide, and epinephrine, tested hierarchically) and symptom recognition (autonomic symptom score, HYPO score, also tested hierarchically) (Aim 1). Factors associated with IAH and the restoration of hypoglycemia awareness will be determined from the screened population and the participants in the trial (Aim 2). A matched control group of healthy non- diabetic controls and of participants with T1D and normal awareness of hypoglycemia will be enrolled to provide normative responses to hypoglycemia at baseline. The study also aims at developing new approaches to diagnosing IAH by testing combinations of self-reported items, CGM-prompted reporting, and physiological monitoring, and predicting responses to intervention using machine learning and artificial intelligence (Aim 3) and at studying brain structure and function associated with and predictive of IAH improvement (Aim 4) using fMRI, with and without hypoglycemia. The ultimate goals of the study are to identify the best treatment for IAH, develop better ways to identify individuals at risk, understand the mechanisms of IAH and, ultimately, to reduce the burden and risks associated with severe hypoglycemia and improve quality of life and treatment satisfaction in patients with T1D.