Using technology to define and mitigate risk of impaired awareness of hypoglycemia in patients with type 1 diabetes

项目总结/摘要 严重低血糖仍然是1型糖尿病患者常见的危及生命的问题 （T1D）。研究一直表明，低血糖意识受损（IAH）的患者， 通常与减弱的反调节反应（CRR）共存，是严重的最高风险 低血糖然而，我们目前没有临床可用的工具来识别IAH患者， 即使发现了这些疾病，我们也缺乏减少其风险的干预措施。这项研究的最终目标是解决 这些巨大的未满足的需求。具体而言，我们计划利用连续葡萄糖监测（CGM）来识别 该CGM度量与IAH和减小的CRR（AIM 1）相关联。然后我们将确定现代 采用混合闭环（HCL）系统的T1D管理可以恢复低血糖意识（AIM 2）。 目的1：确定与低血糖意识相关的CGM指标 我们的第一个假设是CGM测定的低于范围的时间（TBR）与肾上腺素AUC呈负相关 在低血糖钳夹过程中这一假设得到了我们的初步数据的有力支持， 研究策略。为了验证这一假设，我们建议该联盟共招募112名受试者， T1D受试者将在低血糖钳夹前佩戴盲态CGM 10天。收集的数据将 包括低血糖期间的反调节激素、低血糖症状评分（Edinburgh）， 低血糖意识问卷（Clarke、Gold、Pederson和hypo A-Q）。 CGM指标将与CRR、症状评分和当前使用的问卷相关，以定义 意识研究设计将确定哪些CGM指标可预测低血糖意识和CRR。 目的2：确定是否可以使用最新的T1D患者恢复低血糖意识 管理糖尿病 我们的第二个假设是，使用HCL系统的现代糖尿病管理来降低TBR， 提高对低血糖和CRR的认识。为了检验这一假设，所有112名受试者将被随机化 对照组或低血糖减少组1：1，持续2年。在对照组中，所有胰岛素输注 方法将被允许，CGM目标将遵循允许高达4% TBR（~1 小时/天）。低血糖避免组将为所有患者提供HCL系统，目标TBR <1%。 将在基线和第3、6、12、18和24个月时进行低血糖钳夹试验，设盲10天。 每次钳夹前的CGM。主要结果将是肾上腺素AUC在 研究组之间的低血糖钳夹。本研究设计将确定最新的T1D管理是否可以 恢复CRR和低血糖意识。

PROJECT SUMMARY/ ABSTRACT Severe hypoglycemia remains a common and life-threatening issue for patients living with type 1 diabetes (T1D). Research has consistently shown that patients with impaired awareness of hypoglycemia (IAH), which typically coexists with a diminished counterregulatory response (CRR), are at the highest risk for severe hypoglycemia. However, we currently do not have clinically available tools to identify patients with IAH, and even if identified, we lack interventions to reduce their risk. The ultimate goal of this research is to address these large, unmet needs. Specifically, we plan to utilize continuous glucose monitoring (CGM) to identify which CGM metrics are associated with IAH and a diminished CRR (AIM 1). We will then determine if modern T1D management with hybrid closed loop (HCL) systems can restore hypoglycemia awareness (AIM 2). AIM 1: Identify the CGM metrics associated with hypoglycemia awareness Our first hypothesis is that time below range (TBR) by CGM will inversely correlate with epinephrine AUC during a hypoglycemic clamp. This hypothesis is strongly supported by our preliminary data detailed in our research strategy. To test this hypothesis, we propose that the consortium enroll a total of 112 subjects with T1D. Subjects will wear a blinded CGM for 10 days prior to a hypoglycemic clamp. Data to be collected will include counterregulatory hormones during hypoglycemia, hypoglycemia symptom scores (Edinburgh), and hypoglycemic awareness questionnaires (Clarke, Gold, Pederson, and hypo A-Q) as we have previously done. CGM metrics will be correlated with CRR, symptom scores, and currently used questionnaires to define awareness. The study design will determine which CGM metrics predict hypoglycemia awareness and CRR. AIM 2: Determine if hypoglycemia awareness can be restored in individuals with T1D using up-to-date management of diabetes Our second hypothesis is that reducing TBR using modern diabetes management with HCL systems will improve awareness of hypoglycemia and the CRR. To test this hypothesis, all 112 subjects will be randomized 1:1 to either a control arm or a hypoglycemia reduction arm for 2 years. In the control arm, all insulin delivery methods will be allowed and CGM targets will follow current standards of care that allow up to 4% TBR (~1 hour/day). The hypoglycemia avoidance arm will provide all patients with a HCL system and target <1% TBR. Hypoglycemic clamps will be conducted at baseline and months 3, 6, 12, 18, and 24 with 10 days of blinded CGM prior to each clamp. The primary outcome will be the difference in epinephrine AUC during hypoglycemic clamp between study arms. This study design will determine if up-to-date T1D management can restore the CRR and hypoglycemia awareness.