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

项目摘要/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)，但与严重低血糖的风险较高相关，限制了最佳血糖控制。随着时间的推移, 20-30%的T1D患者对低血糖(IAH)的认识受损，最有可能的是 反复严重低血糖的后果。IAH本身就是一个重要的风险因素 随后出现严重低血糖，导致恶性循环，可能造成致命后果。 IAH与对低血糖和脑变化的反调节反应(CRR)减弱有关 结构和功能。利用先进技术降低低血糖发生率(持续 血糖监测[CGM]和胰岛素泵)和有针对性的教育可以改善IAH，但不是完全改善。 先进的胰岛素治疗可减少1型糖尿病队列患者对低血糖的意识受损 (AIDRIAHT1C)试验旨在测试HCL与传感器增强泵(SAP)治疗的疗效 通过减少低血糖所花费的时间来提高对低血糖和CRR的认识。这个 这项研究将招募持续至少10年的T1D成年人的不同人群。参与者将是 使用Hypo评分被归类为患有IAH。患有IAH的患者将以1：1随机分为两组 干预措施，两组都将接受旨在降低低血糖的有针对性的教育计划。 在基线和为期两年的6个月间隔期间，参与者将接受逐步的高胰岛素血症- 降血糖钳。评估12个月的主要结果由以下共同主要终点组成 低血糖的CRR(内源性葡萄糖产生、胰多肽和肾上腺素，经测试 分级)和症状识别(自主症状评分、Hypo评分，也进行分级测试) (目标1)。与IAH和低血糖意识恢复相关的因素将从以下方面确定 筛选人群和试验参与者(目标2)。健康体检者为对照组。 糖尿病对照组和患有T1D且低血糖意识正常的参与者将被登记为 在基线水平提供低血糖的标准应对措施。这项研究还旨在开发新的方法 通过测试自我报告项目、CGM提示报告和生理学报告的组合来诊断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) 在研究与IAH改善相关和预测IAH改善的大脑结构和功能(目标4)时，使用 功能磁共振成像，有无低血糖。 这项研究的最终目标是确定治疗IAH的最佳方法，开发更好的方法来确定 处于危险中的个人，了解IAH的机制，并最终减少相关的负担和风险 伴有严重低血糖的T1D患者生活质量和治疗满意度的提高。

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.