Modeling of Insulin and Glucagon Sensitivity During Exercise in Type 1 Diabetes

项目摘要 本研究的目的是探讨不同强度运动对葡萄糖调节系统的影响 并适合不同类型的运动，包括有氧运动和阻力运动，以开发更好的人工 胰腺（AP）控制系统。这里提出的实验将具体揭示运动如何影响1）非- 胰岛素介导的葡萄糖摄取，2）胰岛素介导的葡萄糖摄取（胰岛素敏感性），3）胰高血糖素反应性， 低血糖期间的胰高血糖素反应性。运动通常会导致低血糖， 1型糖尿病患者由于工作肌肉对葡萄糖摄取的快速增加以及胰岛素水平的增加， 灵敏度迄今为止，使用当前的闭环系统避免运动诱发的低血糖的成功有限， 大多数AP算法被设计为对感测到的葡萄糖的下降做出反应，并且这种下降可以从 运动的开始。在这个项目中，我们建议在运动中和运动后评估胰岛素和胰高血糖素的敏感性 进行示踪研究。在第一项研究中，26名患有1型糖尿病的成年受试者将接受三种单一示踪剂， 进行正常血糖实验，在此期间进行锻炼。受试者将接受静脉注射胰岛素、葡萄糖和 奥曲肽（抑制内源性激素的产生），并将定期抽血进行测量 胰岛素、天然葡萄糖、示踪葡萄糖、儿茶酚胺和脂肪酸水平。葡萄糖控制将由 OHSU开发的输注算法。受试者将以三种胰岛素输注速率重复该实验， 低、中、高。示踪剂水平将用于确定以下物质的出现率（Ra）和消失率（Rd）： 葡萄糖，以评估运动期间的葡萄糖摄取。13名受试者将被安排在进行中度有氧运动的手臂中， 而13个将被放置在剧烈有氧运动的手臂上。在第二项研究中，受试者将被带到两个 连续的单示踪剂实验，具有如上所述的用于中度和剧烈有氧运动的双臂。在 在第一个实验中，受试者将保持在正常水平，并给予三个剂量的胰高血糖素，一个在之前，一个在期间，一个在之后。 锻炼后。在第二个实验中，葡萄糖输注速率将在运动期间被限制在初始基础速率， 胰高血糖素将在运动之前、期间和之后给予。将计算Ra和Rd，并用于确定 运动时胰高血糖素敏感性，伴或不伴低血糖。然后重复研究1和2，以确定耐药性 训练而不是有氧运动，因为无氧运动通常与葡萄糖水平的不太显著的变化有关。数据 从这四项研究中，将用于开发一个运动期间血糖调节的综合模型， 集成在模型预测控制（MPC）算法中，用于1型糖尿病患者的胰岛素和胰高血糖素递送的自动控制， 糖尿病在对20名受试者进行的最终交叉研究中，将与运动检测一起测试这种MPC算法。 没有运动检测的类似算法以及用于在自由运动期间控制葡萄糖的传感器增强泵（SAP）， 在一项为期7天的门诊研究中，

Project Summary The objective of this project is to investigate how the glucoregulatory system responds to exercise at different intensities and for different types of exercise including aerobic and resistance for the purpose of developing a better artificial pancreas (AP) control system. The experiments proposed here will specifically reveal how exercise impacts 1) non- insulin mediated glucose uptake, 2) insulin mediated glucose uptake (insulin sensitivity), 3) glucagon responsiveness in euglycemia, and 4) glucagon responsiveness during hypoglycemia. Exercise commonly results in hypoglycemia in persons with type 1 diabetes due to a rapid increase in glucose uptake by working muscles as well as an increase in insulin sensitivity. To date, avoiding exercise-induced hypoglycemia using current closed loop systems has had limited success as most AP algorithms are designed to react to declines in sensed glucose, and this decline may be significantly delayed from the onset of exercise. In this project, we propose to evaluate both insulin and glucagon sensitivity during and after exercise with tracer studies. In the first study, 26 adult subjects with type 1 diabetes will be brought in for three single-tracer, euglycemic experiments during which exercise will be performed. Subjects will receive intravenous insulin, glucose, and octreotide (to suppress endogenous hormone production) and will have blood drawn at regular intervals for measurement of insulin, native glucose, tracer glucose, catecholamine, and fatty acid levels. Glucose control will be managed by an infusion algorithm developed at OHSU. Subjects will repeat this experiment at three insulin infusion rates, designated low, medium, and high. Tracer levels will be used to determine rate of appearance (Ra) and rate of disappearance (Rd) of glucose to assess glucose uptake during exercise. Thirteen subjects will be placed in an arm of moderate aerobic exercise, and 13 will be placed in an arm of intense aerobic exercise. In the second study, subjects will be brought in for two consecutive single-tracer experiments, with two arms as outlined above for moderate and intense aerobic exercise. In the first experiment, subjects will be kept at euglycemia and given three doses of glucagon, one before, one during, and one after exercise. In the second experiment, glucose infusion rate will be clamped at an initial, basal rate during exercise and glucagon will be given before, during, and after exercise. Ra and Rd will be calculated and used to determine changes in glucagon sensitivity during exercise with or without hypoglycemia. Study 1 and 2 will then be repeated for resistance training rather than aerobic as anaerobic exercise is often associated with less dramatic changes in glucose levels. Data from these four studies will be used to develop an integrated model of glucose regulation during exercise that can be integrated in a model predictive control (MPC) algorithm for automated control of insulin and glucagon delivery in type 1 diabetes. In a final crossover study on 20 subjects, this MPC algorithm with exercise detection will be tested alongside a similar algorithm without exercise detection as well as sensor-augmented pumps (SAP) for control of glucose during free- range exercise in a 7 day out-patient study.