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

描述(申请人提供)：与HbA1c一起，1型糖尿病(T1 DM)的血糖变异性(GV)越来越被认为是血糖控制的主要标志。在我们过去的研究中，我们确定了GV的生理和行为相关性，并成功地测试了一种同时降低HbA1c和低血糖风险的生物行为干预措施。这项研究的一个标志性特征是开发并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接受作为动物研究替代品的人体新陈代谢计算机模拟器，以及新的糖尿病助手(DIAS)平台，该平台被用于首个[全球]非卧床人工胰腺试验。我们现在建议继续我们的研究，重点关注以下基本假设：T1 DM的血糖变异性是由挑战代谢系统的行为事件(如进餐、胰岛素注射)触发的。行为挑战的时机和大小，以及代谢机制吸收它们的能力，决定了GV的大小。这一过程在一定的时间框架内发展，可以通过不适当的治疗加速，或者通过精确的时间和剂量的生物行为控制来减弱。这一假说的检验将分三个阶段进行：第一阶段(GV的触发因素)将使用我们广泛的数据库设计血糖变异性综合模型(IMGV)，该模型将：(I)帮助了解错误或不平衡治疗的系统不稳定的时机和程度，以及(Ii)通过广泛的硅实验来协助设计将在第三阶段采用的最佳生物行为干预措施，以澄清系统稳定的时机和前兆。第二阶段(GV的机制)将使用日记、连续血糖监测和现场胰岛素泵记录的组合，并通过基于医院的人体实验室研究来加强，这些研究将澄清行为挑战、生理血糖调节机制和GV之间的关键关系。第三阶段(GV的控制)将在一项随机交叉研究中使用DIAS测试一种旨在逐渐减弱GV的新型步进式生物行为干预的有效性。这种治疗将在血糖控制较差(HbA1c&gt；8.0%)和/或有低血糖风险(有严重低血糖病史的人)的胰岛素泵使用者中进行测试，预计在降低GV方面优于标准的泵疗法。总而言之，该项目将证明：(I)在结合观察性和人体实验室研究的电子实验中，增强了假设的形成/检验，并产生了有效的治疗设计；(Ii)翻译成日常使用的尖端人工胰腺技术优于最先进的当前治疗方法。

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.