Integrated approaches to close the loop in type 1 diabetes

描述(由申请人提供)：项目概要：1型糖尿病闭合循环的综合方法。RFA 08-012强调1型糖尿病(T1 DM)的闭合循环，这一努力将取决于开发生理模型，该模型将使用最先进的技术方法评估血糖变化的原因，以便更好地了解持续皮下胰岛素输注(CSII)算法。生理学研究需要了解由餐后胰岛素作用的昼夜节律和个体内差异、摄入碳水化合物进入体循环的时间和速度的差异以及体力活动变化引起的可变性的影响。我们最近开发并验证了一种三重示踪技术，利用创新的比活度钳将非稳态误差降至最低，以测量餐后外周和肝脏胰岛素的作用以及膳食衍生葡萄糖的出现率。我们还开发并验证了一些工具(如加速计、体力活动监测系统)，以准确地捕捉日常体力活动。在这种背景下，并利用上述技术，我们将解决以下具体目标：1)我们将确定T1 DM患者是否存在餐后胰岛素作用和餐后血糖的昼夜节律模式，以及它与非糖尿病健康人的不同程度。我们还将借此机会进一步开发和验证一种新的单一示踪剂方法来测量餐后血糖动力学。2)我们将探讨胃排空率能否预测T1 DM患者餐后血糖、胰岛素作用和24小时血糖变异性。为此，我们将筛查胃排空异常，然后使用Tripe示踪法(如果在Aim 1中得到验证，则使用单示踪剂模型)来确定无症状的胃排空变化是否伴随着摄入葡萄糖的时间和全身速率的变化，如果是，餐象模式的变化在多大程度上预测餐后高血糖和使用CGM参数测量的血糖变异性。这是一个需要考虑的重要变量，因为在无症状的T1 DM患者中经常观察到胃动力异常。3)我们将评估中、低强度体力活动对T1 DM患者血糖变异性、餐后血糖及胰岛素作用的影响。为此，我们将使用CGM参数(高血糖指数和低血糖指数)、餐后血糖表现和餐后胰岛素作用来评估低强度和中等强度运动(通过加速计测量)对血糖变异性的影响。我们将利用这个机会进一步修改示踪剂技术，如果有必要的话，以阻断特定的活性，以便准确地估计胰岛素在餐后状态下的作用。总结和意义：葡萄糖变异性和频繁的低血糖是限制T1 DM患者最佳皮下胰岛素给药的主要因素。在这一应用中，我们建议利用并进一步创新现有的尖端技术来开发一个生理模型，通过精确的体力活动监测系统(如加速计)捕获餐后胰岛素活动、胃运动和体力活动的每日变化，以便于开发个性化的胰岛素递送“闭环系统”的模型预测控制算法。

DESCRIPTION (provided by applicant): Project Summary Integrated Approaches to close the loop in Type 1 diabetes. The RFA 08-012 emphasizes closing the loop in type 1 diabetes mellitus (T1DM), an endeavor that will depend on developing physiological models that will evaluate the reasons for glycemic variability using state of the art technologic approaches so that continuous subcutaneous insulin infusion (CSII) algorithms are better informed. The physiology studies need to be directed towards understanding the impact of variability introduced by circadian and intra-individual differences in post prandial insulin action, variability in the timing and rate of appearance of ingested carbohydrates into the systemic circulation and variability introduced by changes in physical activity. Using innovative specific activity clamps to minimize non steady state errors, we have recently developed and validated a triple tracer technique to measure post prandial peripheral and hepatic insulin action and rate of appearance of meal derived glucose. We have also developed and validated tools (eg., accelerometers, physical activity monitoring systems) to accurately capture daily physical activity. In this context, and utilizing the above techniques, the following specific aims will be addressed: 1) We will determine whether circadian pattern of post prandial insulin action and meal glucose appearance occurs in T1DM and the extent to which it differs from nondiabetic healthy subjects. We will also take this opportunity to further develop and validate a novel single tracer method to measure post prandial glucose kinetics. 2) We will explore if gastric emptying rate can predict post prandial meal glucose appearance, insulin action and 24 hour glucose variability in T1DM. To do so, we will screen for abnormalities in gastric emptying then use the tripe tracer method (or single tracer model if validated in aim 1) to determine if asymptomatic changes in gastric emptying are accompanied by changes in the timing and systemic rate appearance of ingested glucose and if so, the extent to which changes in the pattern of meal appearance predict post prandial hyperglycemia and glucose variability as measured using CGM parameters. This is an important variable to consider since abnormal gastric motility is frequently observed in asymptomatic individuals with T1DM. 3) We will evaluate the impact of low and moderate intensity physical activity on glucose variability, post prandial meal glucose appearance and insulin action in T1DM. To do so, we will assess the impact of low and moderate intensity exercise (measured by accelerometers) on glucose variability using CGM parameters (high and low blood glucose indices), meal glucose appearance and post prandial insulin action. We will take this opportunity to further modify tracer technique if necessary to clamp specific activity in order to accurately estimate insulin action in the post prandial state. Summary and Significance: Glucose variability and frequent hypoglycemia are major factors that limit optimal subcutaneous insulin delivery in T1DM. In this application, we propose to utilize and further innovate existing cutting edge techniques to develop a physiological model whereby daily variations in post prandial insulin action, gastric motility and physical activity captured with precise physical activity monitoring systems, e.g., accelerometers, are integrated to facilitate development of a model predictive control algorithm of individualized "closed loop system" of insulin delivery.