Optimization of an Adaptive Dual-Hormone External Endocrine Pancreas.

描述（由申请人提供）：主要研究者Joseph El Youssef博士在俄勒冈州健康与科学大学（OHSU）Kenneth Ward、Andrew Ahmann和Charles Roberts博士的指导下，将开展题为“自适应双激素外分泌胰腺的优化”的项目。利用俄勒冈州临床和转化研究所（OCTRI）和OHSU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，该系统根据皮下插入的连续葡萄糖监测仪获得的葡萄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的临床研究技能的进步，并辅以人类研究计划（HIP）证书计划中的OHSU课程，旨在教育和培养临床和转化研究中的年轻研究人员。El Youssef博士将设计和开展动物研究，旨在测试胰岛素和胰高血糖素新型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纽约州特洛伊的伦斯勒理工学院学习计算机编程和控制理论，由长期合作者韦恩贝奎特博士教授，他还将提供控制理论和建模和仿真所需的软件工具的指导。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，这是该领域独立发展的重要要求。Jaeb健康研究中心的John Lum先生同意与El Youssef博士合作，提供FDA批准的300人模拟器，用于测试El Youssef博士熟悉的算法更新。该提案的临床方面是在五年的指导项目中，在1型糖尿病患者中连续改进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）通过创建设计用于快速起效的无锌胰岛素制剂的“进餐模式”组件来减少餐前开环胰岛素输送（Linjeta，来自Biodel，Inc）;（c）开发全身胰高血糖素模型并将其并入算法中以优化算法要求胰高血糖素递送的方式，以便最大化低血糖症预防并最小化肝糖原消耗。在1型糖尿病受试者中进行的具有适当把握度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人员，专注于闭环胰岛素/胰高血糖素输送系统，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做出持续贡献。

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.