Closed-Loop Effectiveness and Ambulatory Regimens (CLEAR)

描述（由申请人提供）：1型糖尿病（T1 D）管理的技术改进，包括胰岛素类似物、胰岛素泵治疗和最近的动态血糖监测，仍不足以使大多数T1 D患者的血糖水平正常化。很可能没有手动的“开环”治疗性胰岛素方案能够最佳地控制T1 D患者的胰岛素分泌，并且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，包括精确输送可变量胰岛素的胰岛素泵、精确确定葡萄糖水平的连续葡萄糖传感器以及基于实时葡萄糖读数确定胰岛素输送速率的有效算法，仍然是减少高血糖和低血糖暴露的最有希望的干预措施。在成人和青少年中进行的短期医院研究已经证明了这种方法的可行性。然而，当前闭环方法的缺陷已经变得明显。目前的皮下胰岛素递送方法不足以快速防止血糖水平的膳食相关增加，并且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，住院研究无法真实地复制通常家庭环境中固有的膳食和活动的可变性。本研究项目的目标有两个：（1）优化闭环系统的性能，采用加速皮下胰岛素输送或延迟碳水化合物吸收的策略，从而改善餐时血糖控制并潜在地限制低血糖;和（2）评价在流动环境中闭环输送的安全性和有效性，使用逐步增加远程计算机化和无线通信技术的利用并减少对受试者监测的传统方法的依赖的逐步方法。计划中的实验将建立在我们在胰岛素药代动力学和药效学以及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。拟议的研究是新颖的，重要的，并可能推进我们的理解，不仅闭环控制T1 D，而且其潜在的用途作为治疗低血糖无意识。 公共卫生相关性：对于大约1/700的美国1型糖尿病患者，推荐的强化治疗是困难的，负担沉重的，而且往往不足以预防长期并发症和发病率。自动反馈、葡萄糖控制、胰岛素输送系统的开发将有效地调节血糖水平，这将改善患者的预后和生活质量，并可能降低社会医疗保健成本。

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.