Biobehavioral Triggers, Mechanisms, and Control of Glucose Variability in T1DM

描述（由申请方提供）：沿着HbA 1c，1型糖尿病（T1 DM）中的葡萄糖变异性（GV）越来越被视为血糖控制的主要标志物。在我们过去的研究中，我们确定了GV的生理和行为相关性，并成功地测试了同时降低HbA 1c和低血糖风险的生物行为干预。这项研究的一个标志性特征是开发和依赖复杂的计算机模型和先进技术，例如迄今为止唯一被FDA接受的人体代谢计算机模拟器，作为动物研究的替代品，以及新的糖尿病助手（DiAs）平台，该平台用于第一次[全球]非卧床人工胰腺试验。我们现在建议通过关注以下基本假设继续研究：T1 DM中的葡萄糖变异性是由挑战代谢系统的行为事件（例如进餐、胰岛素注射）触发的。行为挑战的时间和程度，以及代谢机制吸收它们的能力，决定了GV的大小。这个过程在一定的时间范围内发展，并且可以通过不充分的治疗来加速，或者通过精确的时间和生物行为控制的剂量来减弱。对这一假设的检验将分三个阶段进行：（GV的触发器）将使用我们广泛的数据库来设计葡萄糖变异性的综合模型（IMGV），该模型将：（I）帮助理解时机不当或不平衡治疗造成系统不稳定的时机和程度，和（ii）通过大量的硅内实验澄清系统稳定的时间和前体，帮助设计将在第3阶段中采用的最佳生物行为干预。第2阶段（GV的机制）将结合使用日记、连续血糖监测和现场胰岛素泵记录，并通过基于医院的人体实验室研究进行增强，这将阐明行为挑战、生理葡萄糖调节机制和GV之间的关键关系。第3阶段（GV控制）将在随机交叉研究中使用DiAs测试旨在逐渐减弱GV的新型逐步生物行为干预的有效性。该治疗将在血糖控制不佳（HbA 1c>8.0%）和/或有低血糖风险（有严重低血糖病史）的胰岛素泵使用者中进行测试，预计在降低GV方面上级标准泵治疗。总之，该项目将证明：（I）计算机实验结合观察和人类实验室研究，增强了假设制定/测试，并导致有效的治疗设计;（ii）转化为日常使用的尖端人工胰腺技术上级最先进的当前治疗方法。 公共卫生相关性：1型糖尿病中葡萄糖变异性的生物行为触发因素、机制和控制项目叙述1型糖尿病中的葡萄糖变异性（GV）越来越被认为是血糖控制的主要标志物，可能与HbA 1c反映的慢性高血糖一起沿着，导致大量糖尿病并发症。因此，研究必须集中在（一）触发器和机制，导致增加GV，和（ii）的方法控制GV。我们现在提出了一个跨学科的项目，使用人类实验室和现场研究和复杂的计算机模拟来阐明GV的行为触发和生理机制之间的相互作用，并设计和测试一个逐步的行为反馈干预，专门针对减少GV在患者的自然环境。据设想，这种跨学科的方法将加强假设的制定和测试，并将促进有效的硅内治疗设计，可以转化为其他研究和临床实践。

DESCRIPTION (provided by applicant): Along with HbA1c, glucose variability (GV) in type 1 diabetes (T1DM) is increasingly regarded as a primary marker of glycemic control. In our past studies we identified physiological and behavioral correlates of GV and successfully tested a biobehavioral intervention reducing simultaneously HbA1c and the risk for hypoglycemia. A signature characteristic of this research was the development of, and the reliance upon, sophisticated computer models and advanced technology, e.g. the only to date computer simulator of the human metabolism accepted by the FDA as a substitute to animal studies and the new Diabetes Assistant (DiAs) platform, which was used in the first [Worldwide] trials of ambulatory artificial pancreas. We now propose to continue our investigations by focusing on the following fundamental hypothesis: Glucose variability in T1DM is triggered by behavioral events (e.g. meals, insulin injection) that challenge the metabolic system. The timing and the magnitude of the behavioral challenges, and the ability of the metabolic mechanisms to absorb them, determine the magnitude of GV. This process develops in a certain time frame, and can be accelerated by inadequate treatment, or attenuated by precise timing and dosing of bio- behavioral control. The testing of this hypothesis will proceed in three phases: Phase 1 (triggers of GV) will use our extensive database to design an Integrated Model of Glucose Variability (IMGV), which will: (I) help understand the timing and the magnitude of system destabilization with mistimed or unbalanced treatment, and (ii) assist the design of an optimal biobehavioral intervention to be employed in Phase 3 by extensive in silicon experiments clarifying the timing and the precursors of system stabilization. Phase 2 (mechanisms of GV) will use a combination of diaries, continuous glucose monitoring, and insulin pump records in the field, augmented by hospital-based human lab studies, which will clarify key relationships between behavioral challenges, physiological glucoregulatory mechanisms, and GV. Phase 3 (control of GV) will test, using DiAs in a randomized cross-over study, the effectiveness of a novel stepwise biobehavioral intervention designed to gradually attenuate GV. This treatment will be tested in insulin pump users at poor glycemic control (HbA1c>8.0%) and/or at risk for hypoglycemia (those with history of severe hypoglycemia), and is expected to be superior to standard pump therapy in terms of reduction of GV. In summary, this project will demonstrate that: (I) in silico experiments combined with observational and human lab studies enhance hypothesis formulation/testing, and result in efficient treatment design; (ii) cutting-edge artificial pancrea technology translated for everyday use is superior to state-of-the art current treatments. PUBLIC HEALTH RELEVANCE: Biobehavioral Triggers, Mechanisms, and Control of Glucose Variability in T1DM Project Narrative Glucose variability (GV) in type 1 diabetes is increasingly regarded as a primary marker of glycolic control, potentially responsible, along with chronic hyperglycemia reflected by HbA1c, for a host of diabetes complications. Research must therefore focus on (I) the triggers and the mechanisms leading to increased GV, and (ii) methods for control of GV. We now propose an interdisciplinary project using human laboratory and field studies and sophisticated computer simulation to elucidate the interplay between behavioral triggers and physiological mechanisms of GV, and to design and test a stepwise behavioral-feedback intervention specifically targeting reduction of GV in patients' natural environment. In is envisioned that this interdisciplinary approach will enhance hypothesis formulation and testing, and will promote efficient in-silicon treatment designs that can be translated to other research studies and into the clinical practice.