Integrated approaches to close the loop in type 1 diabetes

描述（由申请人提供）：项目总结综合方法，以关闭1型糖尿病的循环。RFA 08-012强调关闭1型糖尿病（T1 DM）的闭环，这一奋进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价血糖变异性的原因，以便更好地了解连续皮下胰岛素输注（CSII）算法。生理学研究需要针对理解由昼夜节律和餐后胰岛素作用的个体内差异引入的变异性的影响、摄入的碳水化合物进入体循环的时间和速率的变异性以及由体力活动变化引入的变异性。使用创新的比活度钳，以尽量减少非稳态误差，我们最近开发和验证了一种三重示踪技术，以测量餐后外周和肝脏胰岛素的作用和出现率的膳食衍生葡萄糖。我们还开发并验证了工具（例如，加速度计、身体活动监测系统），以准确地捕捉日常身体活动。在这种情况下，并利用上述技术，将解决以下具体目标：1）我们将确定餐后胰岛素作用和餐后葡萄糖出现的昼夜节律模式是否发生在T1 DM中，以及它与非糖尿病健康受试者的差异程度。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葡萄糖动力学。2)我们将探讨胃排空率能否预测T1 DM患者餐后血糖的出现、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，然后使用胃肠道示踪法（或单一示踪剂模型，如果在目标1中验证）以确定胃排空的无症状变化是否伴随着摄取葡萄糖的时间和全身速率出现的变化，如果是，进餐外观模式的变化预测餐后高血糖和血糖变异性的程度，如使用CGM参数测量的。这是一个需要考虑的重要变量，因为在无症状T1 DM患者中经常观察到胃动力异常。3)我们将评估低强度和中等强度体力活动对T1 DM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评估低强度和中等强度运动（通过加速度计测量）对血糖变异性的影响。我们将借此机会进一步修改示踪技术，如果有必要钳制比活性，以准确估计餐后状态下的胰岛素作用。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输注的主要因素。在本申请中，我们提出利用并进一步创新现有的尖端技术来开发生理模型，由此利用精确的身体活动监测系统捕获餐后胰岛素作用、胃动力和身体活动的每日变化，例如，集成了加速计，以便于开发胰岛素输送的个体化“闭环系统”的模型预测控制算法。 公共卫生相关性：胰岛素泵和葡萄糖探头对1型糖尿病（T1 DM）患者血糖控制和生活质量的影响有限。这是因为对胰岛素作用效率、胃排空能力和体力活动的每日变化对T1 DM患者血糖每日波动的影响了解有限。利用创新和尖端技术，我们将通过胰岛素泵和葡萄糖传感器研究所有这些因素对T1 DM患者糖代谢和血糖波动的影响，同时开始使用高精度加速度计等新技术来捕获身体活动。我们相信，从我们的研究中获得的信息将导致第一代内分泌人工胰腺的发展。

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.