Closed-Loop Effectiveness and Ambulatory Regimens (CLEAR)

描述（由申请人提供）：1型糖尿病（T1D）管理的技术改进，包括胰岛素类似物，胰岛素泵治疗，以及最近的连续血糖监测，仍然不足以使大多数T1D患者的血糖水平正常化。很可能没有手动的“开环”胰岛素治疗方案能够最佳地控制T1D患者的血糖，生物胰岛细胞替代目前是不可行的。“闭环”自动化人工胰腺系统由胰岛素泵组成，用于精确输送可变量的胰岛素，连续葡萄糖传感器用于精确测定葡萄糖水平，有效算法用于根据实时葡萄糖读数确定胰岛素输送率，仍然是最有希望减少高血糖和低血糖暴露的干预措施。在成人和青少年中进行的短期医院研究证明了这种方法的可行性。然而，目前的闭环方法的缺陷已经变得明显。目前的皮下胰岛素输送方法不足以快速预防与饮食相关的血糖水平升高，血浆胰岛素水平的持续升高与随后的低血糖风险相关。最重要的是，住院病人的研究不能真实地复制通常家庭环境中固有的饮食和活动的可变性。本研究项目的目标有两个：(1)优化闭环系统的性能，使用加速皮下胰岛素输送或延迟碳水化合物吸收的策略，从而改善膳食葡萄糖控制并可能限制低血糖；(2)通过逐步增加远程计算机和无线通信技术的利用，减少对传统受试者监测方法的依赖，评估门诊环境下闭环分娩的安全性和有效性。计划中的实验将建立在我们在胰岛素药代动力学、药效学和葡萄糖反调节方面的专业知识基础上，并受益于我们正在进行的行业合作。提出的研究是新颖的，重要的，不仅可能促进我们对T1D闭环控制的理解，而且可能促进其作为低血糖无意识治疗的潜在应用。

DESCRIPTION (provided by applicant): Technological Improvements in the management of type 1 diabetes (T1D), including insulin analogs, insulin pump therapy, and most recently, continuous glucose monitoring, are still not sufficient to normalize glucose levels in most people with T1D. It is likely that no manual, "open-loop" therapeutic insulin regimen will be able to optimally control glycemia in patients with T1D, and biological islet-cell replacement is presently unfeasible. "Closed-loop" automated artificial pancreas systems, consisting of an insulin pump to precisely deliver variable amounts of insulin, a continuous glucose sensor to accurately determine the glucose levels, and effective algorithms to determine insulin delivery rates based on real-time glucose readings, remains the most promising intervention to reduce hyperglycemic and hypoglycemic exposures. Short-duration hospital-based studies in adults and adolescents have demonstrated feasibility of this approach. However, deficiencies in current closed-loop approaches have become apparent. Present methods of subcutaneous insulin delivery are not sufficiently rapid to prevent meal-related increases in blood glucose levels, and persistent elevations in plasma insulin levels are associated with a risk of subsequent hypoglycemia. Most importantly, inpatient studies cannot realistically replicate the variability of meals and activities inherent in the usual home environment. The objectives of this research project are twofold: (1) to optimize the performance of closed-loop systems using strategies to either accelerate subcutaneous insulin delivery or delay carbohydrate absorption, thereby allowing improved prandial glucose control and potentially limiting hypoglycemia; and (2) to evaluate the safety and effectiveness of closed-loop delivery in the ambulatory environment, using a stepwise approach that gradually increases utilization of remote computerized and wireless communication techniques and decreases reliance on traditional methods of subject monitoring. The planned experiments will build on our expertise in insulin pharmacokinetics and pharmacodynamics and glucose counter-regulation and benefit from our ongoing industry collaborations. The proposed studies are novel, important, and likely to advance our understanding not only of closed-loop control of T1D, but also its potential use as a treatment for hypoglycemia unawareness. PUBLIC HEALTH RELEVANCE: For the approximately 1 in 700 Americans with type 1 diabetes, recommended intensive treatments are difficult, burdensome, and frequently insufficient to prevent long-term complications and morbidity. Development of automated feedback, glucose-controlled, insulin delivery systems that would effectively regulate blood sugar levels would lead to improvements in patient outcomes and quality of life, and potentially, reduction in societal health care costs.