Novel Glucagon Modulators and the Closed Loop System

描述(由申请人提供)：针对1型糖尿病(T1 DM)的高血糖可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，特别是进餐。完全集成的闭环系统，由连续血糖监测和葡萄糖响应型胰岛素给药组成，有望成为“智能胰岛素泵”。理想的闭环系统将不再需要用户输入。然而，目前的闭环系统不能及时对一顿饭做出反应，胰岛素单一疗法也无法解决餐后高血糖问题。矛盾的是，T1 DM患者餐后高血糖与餐后高血糖相关。胰升糖素抑制药，如胰淀素类似物普拉林肽和胰升糖素样肽-1(GLP-1)模拟物埃塞那肽，是被批准用于糖尿病的新药物。胰淀素是与胰岛素共同分泌的第二种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降低餐后即刻的高血糖。激素GLP-1具有与胰淀素类似的作用，也可能对T1 DM有益。这项提议的总体目标是将闭环系统技术与这些荷尔蒙结合起来，这些荷尔蒙对餐后血糖稳态至关重要。在方案1中，我们将在完全闭环设置下研究20名T1 DM受试者。受试者将被随机接受普拉林肽或埃塞那肽作为餐前推注。我们假设，辅助性普美林肽/艾塞那肽治疗的餐后血糖浓度将比单独使用胰岛素更好。方案2，将测试在闭合循环设置中连续使用普拉林肽和胰岛素与单独使用胰岛素的可行性。美敦力是开发血糖控制闭环系统技术的领先者，赫普图拉博士率先将普拉林肽和埃塞那肽用于治疗T1 DM。这些方案将定义这些激素在闭合循环环境中餐后血糖稳态中的作用。此外，这项试验有可能导致第二代闭环系统与多种激素输送。这些方案将对现有的临床指南产生直接影响，甚至在闭环系统商业化之前就会改善血糖。 公共卫生相关性：闭环系统为1型糖尿病患者提供了一种更好的疾病管理方法，通过持续监测血糖和胰岛素输送，而不需要患者干预。然而，这种方法不能以最优的方式响应餐后血糖的变化，导致餐后血糖漂移高于预期。普拉林肽和埃塞那肽是与膳食相关的激素，在糖尿病中没有得到适当的调节；这项建议测试了这些激素在闭合循环系统中的使用，以解决与膳食相关的高血糖问题。

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.