Optimization of an Adaptive Dual-Hormone External Endocrine Pancreas.

描述（由申请人提供）：首席研究员Joseph El Youssef博士。俄勒冈健康与科学大学（OHSU）的Kenneth Ward、Andrew Ahmann和Charles Roberts将承担这个名为“适应性双激素外部内分泌胰腺的优化”的项目。利用俄勒冈临床与转化研究所（OCTRI）和俄勒冈州立大学比较医学系的服务，El Youssef博士打算提高自适应闭环系统的效率，该系统可以根据皮下插入的连续血糖监测仪获得的血糖水平，自动向糖尿病患者皮下输送胰岛素和胰高血糖素。这些研究将有助于他临床研究技能的进步，辅以OHSU人类调查计划（HIP）证书课程的课程，旨在教育和培养临床和转化研究的年轻研究者。El Youssef博士将设计并开展动物研究，旨在测试新型胰岛素和胰高血糖素制剂的药代动力学和动力学特性，以改善闭环血糖控制。此外，El Youssef博士将在波特兰州立大学和位于纽约州特洛伊的伦斯勒理工学院（Rensselaer Polytechnic Institute）学习计算机编程和控制理论方面的技能，由长期合作伙伴Wayne Bequette博士授课，他还将提供控制理论和建模和仿真所需软件工具方面的指导。这些课程将为El Youssef博士提供算法开发和系统建模方面的经验，这是在该领域独立发展的重要要求。杰布健康研究中心（Jaeb Center for Health Research）的约翰·林（John Lum）已同意与埃尔优素福博士合作，提供fda批准的300人模拟器，用于测试算法更新，埃尔优素福博士对此很熟悉。该建议的临床方面是在5年的指导项目中，在1型糖尿病患者中不断完善自适应比例导数算法的迭代。闭环血糖控制系统的预期改进将包括：(a)使该系统适应皮质类固醇诱导的胰岛素抵抗和运动诱导的胰岛素敏感性增加；(b)通过创造一种设计用于快速起效的无锌胰岛素制剂的“用餐模式”成分，减少餐前开环胰岛素输送（Linjeta，来自Biodel， Inc）；(c)建立一个全身胰高血糖素模型，并将其纳入算法，优化算法调用胰高血糖素的方式，以最大限度地预防低血糖，最大限度地减少肝糖原消耗。在1型糖尿病患者中进行适当的研究将解决这些问题。随着这个指导项目的结束，El Youssef博士将成为糖尿病学的独立研究员，专注于胰岛素/胰高血糖素闭环输送系统，并发展成为一名医生科学家，可以在1型糖尿病患者的自动血糖控制领域提供持续的贡献。

DESCRIPTION (provided by applicant): The Principal Investigator, Dr. Joseph El Youssef, under the mentorship of Drs. Kenneth Ward, Andrew Ahmann and Charles Roberts at the Oregon Health and Science University (OHSU), will undertake the project entitled "Optimization of an Adaptive Dual-Hormone External Endocrine Pancreas". Utilizing the services of the Oregon Clinical and Translational Research Institute (OCTRI), and the Department of Comparative Medicine at OHSU, Dr. El Youssef intends to improve the efficiency of an adaptive closed loop system which automatically delivers insulin and glucagon subcutaneously to persons with diabetes in response to glucose levels obtained by subcutaneously inserted continuous glucose monitors. These studies will assist in the progression of his clinical research skills, supplemented by an OHSU course in the Human Investigation Program (HIP) certificate program, designed to educate and develop young investigators in clinical and translational research. Dr. El Youssef will design and carry out animal studies geared towards testing the pharmacokinetic and dynamic properties of novel preparations of insulin and glucagon, in order to improve closed-loop glycemic control. In addition, Dr. El Youssef will develop skills in computer programming and control theory, with classes at Portland State University and at the Rensselaer Polytechnic Institute in Troy, NY, taught by long-term collaborator Dr. Wayne Bequette, who will also provide instruction in control theory and the software tools needed for modeling and simulation. These courses will provide Dr. El Youssef with experience in algorithm development and system modeling, important requirements for independent progression in this field. Mr. John Lum at the Jaeb Center for Health Research has agreed to collaborate with Dr. El Youssef, providing access to the FDA-approved 300 person simulator for testing of algorithm updates, with which Dr. El Youssef is familiar. The clinical aspect of the proposal is to successively refine iterations of the Adaptive Proportional Derivative algorithm in persons with Type 1 diabetes over the five years of the mentored project. The anticipated improvements in the closed loop glycemic control system will include: (a) adapting the system for corticosteroid-induced insulin resistance and for exercise-induced increases in insulin sensitivity; (b) reducing pre-meal open-loop insulin delivery by creating a "meal mode" component designed for use with a faster-onset zinc-free insulin preparation (Linjeta, from Biodel, Inc); (c), developing a total-body glucagon model and incorporating it into the algorithm to optimize the way in which the algorithm calls for glucagon delivery in order to maximize hypoglycemia prevention and to minimize hepatic glycogen depletion. Appropriately-powered studies in subjects with Type 1 diabetes will address each of these questions. As this mentored project comes to a close, Dr. El Youssef will become an independent researcher in diabetology, with a focus on closed-loop insulin/glucagon delivery systems, and developing into a physician-scientist who can provide ongoing contributions in the field of automated glycemic control in persons with Type 1 diabetes.