Restoring awareness of hypoglycemia in type 1 diabetes

项目摘要/摘要 这项名为“恢复1型糖尿病患者低血糖意识”的应用程序旨在阐明 完成24个月的1型糖尿病患者对低血糖(IAH)意识受损的异质性 序贯多重分配随机试验(SMART)旨在更好地帮助我们了解 影响抗逆调节防御系统恢复的临床和生理因素 对教育、技术和药物干预的低血糖反应。鉴于坚持不懈的 低血糖阻碍实现对大多数类型性糖尿病患者的适当血糖控制 1糖尿病，迫切需要进一步了解导致1型糖尿病低血糖的机制。 糖尿病，以促进可能实现接近正常血糖控制的益处的治疗方法 没有伴随严重低血糖的风险。本提案的目的是1)确定是否 长期低血糖患者对高胰岛素低血糖钳夹的反调节反应可以恢复 使用实施最新状态的适应性随机临床试验设计的1型糖尿病和IAH ART干预措施，包括低血糖避免教育(标准护理；SOC)、自动胰岛素 采用混合闭环技术(HCL)和新的小剂量胰高血糖素(MDG)药理提供；2) 确定与干预后改善的反调节反应相关的生理因素， 包括但不限于年龄、糖尿病病程和持续血糖监测(CGM)指标；以及3) 验证HypoA-Q简式问卷作为自我报告方法的有效性，以确定IAH 来自降血糖钳夹的反调节反应。拟议的智能书房设计将 允许严格地确定改善以下两种情况所需的低血糖避免程度 逆调节肾上腺素和自主神经症状对胰岛素诱导的低血糖的反应以及 其他因素，如年龄、糖尿病病程、其他CGM指标和有效的IAH自我报告，可能 预测个体对SOC、HCL和千年发展目标干预的反应。

PROJECT SUMMARY / ABSTRACT This application “Restoring awareness of hypoglycemia in type 1 diabetes” proposes to elucidate the heterogeneity of impaired awareness of hypoglycemia (IAH) in type 1 diabetes through completion of a 24-month Sequential Multiple Assignment Randomized Trial (SMART) designed to better inform our understanding of the clinical and physiologic factors which contribute to restoration of counterregulatory defenses against hypoglycemia in response to educational, technologic, and pharmacologic interventions. Given the persistent barrier of hypoglycemia to the realization of achieving adequate glycemic control for most individuals with type 1 diabetes, there is a critical need to further understand the mechanisms contributing to hypoglycemia in type 1 diabetes in order to advance treatment approaches that may realize the benefits of near-normal glycemic control without the accompanying risk for severe hypoglycemia. The present proposal aims 1) to determine whether counterregulatory responses to a hyperinsulinemic hypoglycemic clamp can be restored in individuals with long standing type 1 diabetes and IAH using an adaptive randomized clinical trial design implementing state-of-the- art interventions including hypoglycemia avoidance education (standard-of-care; SOC), automated insulin delivery with hybrid closed loop technology (HCL), and novel mini-dose glucagon (MDG) pharmacology; 2) to determine the physiological factors associated with improved counterregulatory responses following intervention, including but not limited to age, diabetes duration, and continuous glucose monitoring (CGM) metrics; and 3) to validate a HypoA-Q short form questionnaire as a self-report measure for identifying IAH with measurement of counterregulatory responses derived from the hypoglycemic clamp. The proposed SMART study design will allow for rigorously determining both the degree of hypoglycemia avoidance necessary for improvement of counterregulatory epinephrine and autonomic symptom responses to insulin-induced hypoglycemia, as well as the additional factors such as age, diabetes duration, other CGM metrics, and validated IAH self-report that may predict individual responsiveness to SOC, HCL, and MDG interventions.