Integrated approaches to close the loop in type 1 diabetes

描述（由申请人提供）：项目总结：1型糖尿病闭环的综合方法。RFA 08-012强调1型糖尿病（T1DM）的闭合循环，这一努力将依赖于开发生理模型，利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。生理学研究的方向是理解由昼夜节律和餐后胰岛素作用的个体内差异、摄入碳水化合物进入体循环的时间和速率的可变性以及身体活动变化带来的可变性所带来的影响。我们最近开发并验证了一种三重示踪技术，用于测量餐后外周和肝脏胰岛素的作用以及餐源性葡萄糖的出现率。我们还开发并验证了工具(例如。（如加速度计、身体活动监测系统），以准确捕捉每天的身体活动。在这种情况下，利用上述技术，将解决以下具体目标：1)我们将确定T1DM患者餐后胰岛素作用和膳食葡萄糖外观的昼夜节律模式是否发生，以及它与非糖尿病健康受试者的差异程度。我们也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葡萄糖动力学。2)我们将探讨胃排空率是否可以预测T1DM患者餐后血糖表现、胰岛素作用和24小时血糖变异性。为此，我们将筛选胃排空异常，然后使用三联示踪剂方法（或单示踪剂模型，如果在目标1中得到验证）来确定胃排空的无症状变化是否伴随着摄入葡萄糖的时间和全身速率的变化，如果是这样，进餐外观模式的变化在多大程度上预测餐后高血糖和使用CGM参数测量的葡萄糖变异性。这是一个需要考虑的重要变量，因为在无症状的T1DM患者中经常观察到胃运动异常。3)我们将评估低强度和中等强度体力活动对T1DM患者血糖变异性、餐后血糖表现和胰岛素作用的影响。为此，我们将利用CGM参数（高血糖指数和低血糖指数）、膳食葡萄糖外观和餐后胰岛素作用来评估低强度和中等强度运动（通过加速度计测量）对葡萄糖变异性的影响。如果有必要，我们将借此机会进一步改进示踪技术，以箝制特定活性，以便准确估计餐后状态下胰岛素的作用。总结与意义：血糖变异性和频繁的低血糖是限制T1DM患者最佳皮下胰岛素输送的主要因素。在这项应用中，我们建议利用并进一步创新现有的前沿技术来开发一种生理模型，通过精确的身体活动监测系统（如加速度计）捕获餐后胰岛素作用、胃运动和身体活动的日常变化，从而促进胰岛素输送个性化“闭环系统”的模型预测控制算法的开发。

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. PUBLIC HEALTH RELEVANCE: The insulin pump and the glucose sensor have had limited impact on control of blood sugar and quality of life in type 1 diabetes mellitus (T1DM). This is because of limited knowledge of the effects of daily variation in efficiency of insulin action, stomach emptying capacity and physical activity on daily fluctuations in blood sugar in T1DM. Using innovative and cutting edge technologies, we will investigate the effects of all of these factors on sugar metabolism and fluctuations in blood sugar in people with T1DM on the insulin pump and glucose sensor and simultaneously initiate the use of new technology such as highly accurate accelerometers to capture physical activity. We believe that information obtained from our research will result in the development of a first generation endocrine artificial pancreas.