Novel Glucagon Modulators and the Closed Loop System

描述（由申请人提供）：针对1型糖尿病（T1DM）的高血糖，减少糖尿病相关并发症。使用胰岛素泵的生理性胰岛素替代是治疗的黄金标准。这种方法依赖于患者进行血糖监测和胰岛素输送，特别是餐丸。这个完全集成的闭环系统由连续血糖监测和葡萄糖反应胰岛素管理组成，有望成为“智能胰岛素泵”。理想的闭环系统将不需要用户输入。然而，目前闭环系统无法及时对膳食做出反应，胰岛素单药治疗无法解决餐后高血糖问题。矛盾的是，餐后高胰高血糖素血症与T1DM患者餐后高血糖有关。胰高血糖素抑制剂，如胰高血糖素类似物普兰林肽和胰高血糖素样肽-1 （GLP-1）模拟物艾塞那肽，是批准用于糖尿病的新药物。胰淀素是第二种与胰岛素共同分泌的β细胞激素。餐后胰淀素通过抑制胰高血糖素和延缓胃排空来减少餐后高血糖。激素GLP-1具有与胰淀素相似的作用，可能也对T1DM有益。该方案的总体目标是将闭环系统技术与这些对餐后葡萄糖稳态至关重要的激素结合起来。在方案1中，我们将对20名T1DM受试者进行全闭环设置。受试者将随机接受普兰林肽或艾塞那肽作为餐前丸剂。我们假设餐后葡萄糖浓度与辅助普兰林肽/艾塞那肽治疗相比单独使用胰岛素会更好。方案2将测试在闭环环境下连续使用普兰林肽和胰岛素与单独使用胰岛素的可行性。美敦力是开发葡萄糖控制闭环系统技术的领导者，Heptulla博士率先在T1DM中使用普兰林肽和艾塞那肽。这些方案将确定这些激素在闭环环境下餐后葡萄糖稳态中的作用。此外，该试验有可能导致第二代多激素输送闭环系统。这些方案将对现有的临床指南产生直接影响，并将在闭环系统商业化之前改善血糖水平。

DESCRIPTION (provided by applicant): Targeting hyperglycemia in type 1 diabetes mellitus (T1DM) reduces diabetes-related complications. Physiologic insulin replacement using an insulin pump is the gold standard of treatment. This method relies on the patient being engaged in blood glucose monitoring and insulin delivery, especially for meal boluses. The fully integrated closed-loop system, comprised of continuous glucose monitoring and glucose-responsive insulin administration, and holds the promise of an "intelligent insulin pump." The ideal closed-loop system will obviate the need for user input. However, currently the closed-loop system is unable to respond to a meal in a timely fashion and insulin monotherapy fails to address postprandial hyperglycemia. Paradoxically, post-meal hyperglucagonemia is associated with postprandial hyperglycemia in T1DM. Glucagon suppressors such as the amylin analog, pramlintide, and the glucagon like peptide-1 (GLP-1) mimetic, exenatide, are new agents approved for use in diabetes. Amylin is the second beta cell hormone that is co-secreted with insulin. Amylin in the postprandial period reduces immediate postprandial hyperglycemia by suppressing glucagon and delaying gastric emptying. The hormone GLP-1 has similar actions to amylin and may also be beneficial in T1DM. The overall goal of this proposal is to merge the closed-loop system technology with these hormones, which are crucial to postprandial glucose homeostasis. In protocol 1, we will study 20 T1DM subjects with the fully closed-loop setting. Subjects will be randomized to either receive pramlintide or exenatide as a pre-meal bolus. We hypothesize that post-meal glucose concentrations will be better with adjunctive pramlintide/exenatide therapy than insulin alone. Protocol 2, will test the feasibility of continuous pramlintide and insulin in the closed loop setting versus insulin alone. Medtronic is the leader in the development of closed-loop system technology for glucose control and Dr. Heptulla has pioneered the use of pramlintide and exenatide in T1DM. These protocols will define the roles of these hormones in post-prandial glucose homeostasis in the closed loop setting. Moreover, this trial has the potential to lead to second-generation closed-loop system with multiple-hormone delivery. These protocols will have a direct impact on existing clinical guidelines and will improve glycemia even prior to the commercial availability of the closed-loop system. PUBLIC HEALTH RELEVANCE: The closed loop system offers patients with type 1 diabetes a better method of managing their disease by way of continuous monitoring of glucose and delivery of insulin without the need for patient intervention. However, this method is not able to respond to the glucose changes due to a meal in an optimal fashion, resulting in higher than desired after-meal glucose excursions. Pramlintide and exenatide are meal-related hormones that are not appropriately regulated in diabetes; this proposal tests the use of these hormones with the closed loop system to address meal-related high blood glucose.