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

 描述（由申请人提供）：当血糖浓度升高时（例如，响应进食），胰淀素与胰岛素从胰岛β细胞共分泌，而胰高血糖素从胰岛β细胞分泌受到抑制。相反，随着葡萄糖水平下降，胰岛素和胰淀素分泌福尔斯下降，而胰高血糖素分泌增加。体育锻炼也伴随着葡萄糖下降，胰岛素下降和胰高血糖素浓度上升。相反，在1型糖尿病中，由于伴随的细胞功能障碍，在餐后状态下存在高胰高血糖素血症，而在运动期间胰高血糖素反应不足，从而分别诱发餐后高血糖症和运动后低血糖症。最近对闭环人工胰腺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）方法用于1型糖尿病的短期血糖控制，而不试图在这些个体中恢复正常的激素环境。本申请中概述的创新方法寻求通过膳食和体育锻炼尽可能恢复正常的激素环境。使用双腔泵和即将可用的胰岛素和胰淀素类似物普兰林肽作为对照机制的联合制剂，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。普兰林肽的使用将有助于抑制餐后高胰高血糖素血症，改善胰岛素敏感性，从而允许较低的餐时胰岛素剂量。这反过来又可以预防餐后低血糖。胰高血糖素的使用将仅限于作为一种安全救援机制，其将由葡萄糖水平下降触发，特别是在体育锻炼期间和之后。我们还建议将计算的胰岛素敏感性参数（使用普兰林肽和运动期间）使用胰岛素泵输注速率和CGM衍生的葡萄糖波动来告知算法，在计算机实验中测试其安全性，提炼三种荷尔蒙（胰岛素+普兰林肽+胰高血糖素）算法，并最终测试其在长期临床试验中与单药相比的疗效。（仅菊粉）和双激素（胰岛素+普兰林肽）算法。 因此，所提出的研究纳入了几项创新，包括：在闭环研究中应用胰岛素敏感性参数;使用胰岛素-普兰林肽作为模拟健康胰岛β细胞的对照机制;使用胰岛素-普兰林肽组合改善餐后高胰高血糖素血症;使用胰高血糖素仅作为紧急低血糖症的救援机制，特别是在健康时发生的运动期间，从而模仿健康的α细胞;最后也是最重要的是，在长期的家庭临床试验中，测试三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.