Relative Efficacy of Single-, Bi-, and Tri-Hormonal Closed-Loop Control Systems

 描述(申请人提供)：当血糖浓度升高时(例如，对膳食的反应)，胰淀素与来自？细胞的胰岛素共同分泌，而从a细胞分泌的胰升糖素被抑制。相反，随着血糖水平的下降，胰岛素和胰淀素的分泌减少，而胰高血糖素的分泌增加。体育锻炼还伴随着血糖下降、胰岛素下降和胰高血糖素浓度上升。相比之下，在1型糖尿病中，由于伴有细胞功能障碍，餐后状态下存在高血糖素血症，运动时胰高血糖素反应不足，从而分别容易发生餐后高血糖和运动后低血糖。最近关于人工胰腺闭环系统的研究已经应用单激素(仅胰岛素)或双激素(胰岛素+胰高血糖素)方法对1型糖尿病患者进行短期血糖控制，而不试图在进餐和锻炼期间恢复这些人的正常激素环境。本申请中概述的创新方法寻求尽可能恢复正常的荷尔蒙环境，包括用餐和体育锻炼。使用双室泵和即将可用的胰岛素和胰淀素类似物普拉林肽的联合制剂作为控制机制，我们的目标是在1型糖尿病参与者中重建正常的餐后激素谱。普拉林肽的使用将有助于抑制餐后高血糖，改善胰岛素敏感性，从而允许较低的餐后胰岛素剂量。这反过来应该可以防止晚期的餐后低血糖。胰升糖素的使用将受到限制，仅作为一种安全救援机制，这种机制将由血糖水平下降引发，特别是在体育锻炼期间和之后。我们还建议使用胰岛素泵输注率和CGM衍生的葡萄糖漂移来应用计算的胰岛素敏感性参数(使用普拉林肽和运动时)来告知算法，在电子实验中测试其安全性，改进三激素(胰岛素+普拉林肽+胰升糖素)算法，并最终在长期临床试验中测试其有效性，与单一激素(仅限菊粉)和双激素(胰岛素+普拉林肽)算法进行比较。因此，拟议的研究纳入了几项创新，包括：在闭合循环研究中应用胰岛素敏感性参数；使用胰岛素-普拉林肽作为控制机制来模拟健康的ü细胞；使用胰岛素-普拉林肽联合使用来改善餐后高血糖；仅将高血糖素用作即将发生的低血糖的救援机制，特别是在运动期间，如在健康中发生的，从而模仿健康的细胞；最后，也是最重要的，在家庭的长期临床试验中测试三种激素方法与当代单激素和双激素系统的比较。

 DESCRIPTION (provided by applicant): When blood glucose concentrations rise (e.g., in response to meals), amylin is co-secreted with insulin from the ß cells while glucagon secretion from the a cells is inhibited. Conversely, as glucose levels decline, insulin and amylin secretion falls while glucagon secretion increases. Physical exercise is also accompanied by falling glucose, falling insulin and rising glucagon concentrations. In contrast, in Type 1 diabetes, due to concomitant a cell dysfunction, there is hyperglucagonemia in the postprandial state and inadequate glucagon response during exercise thereby predisposing to postprandial hyperglycemia and post exercise hypoglycemia respectively. Recent studies with closed loop artificial pancreas systems have applied single-hormone (insulin only) or dual hormone (insulin + glucagon) approaches for short term glucose control in type 1 diabetes without attempting to restore normal hormonal milieu in these individuals during meals and exercise. The innovative approach outlined in this application seeks to restore, to the extent possible, normal hormonal milieu with meals and physical exercise. Using dual-chamber pumps and imminently available co-formulation of insulin and the amylin analogue pramlintide as a control mechanism, we aim to recreate normal postprandial hormonal profile in type 1 diabetes participants. The use of pramlintide will help suppress postprandial hyperglucagonemia, improve insulin sensitivity thus permitting a lower prandial dose of insulin. That in turn should prevent late postprandial hypoglycemia. The use of glucagon will be limited only as a safety-rescue mechanism that will be triggered by declining glucose levels especially during and after physical exercise. We also propose to apply the computed insulin sensitivity parameters (with pramlintide and during exercise) using the insulin pump infusion rates and CGM derived glucose excursions to inform the algorithm, test its safety in silico experiments, refine the tri-hormonal (insulin + pramlintid + glucagon) algorithm and eventually test it's efficacy in a long-term clinical trial vs. single- (inulin only) and bi- hormonal (insulin + pramlintide) algorithms. The proposed studies therefore incorporate several innovations that include the following: application of insulin sensitivity parameters during closed loop studies; use of insulin-pramlintide as a control mechanism to mimic the healthy ß cell; amelioration of postprandial hyperglucagonemia with use of insulin-pramlintide combination; use of glucagon only as a rescue mechanism for impending hypoglycemia especially during exercise as occurs in health thus mimicking the healthy a cell; finally and most importantly testing the tri- hormonal approach versus contemporary single- and bi-hormonal systems in a long term at home clinical trial.