Novel Glucagon Modulators and the Closed Loop System

新型胰高血糖素调节剂和闭环系统

基本信息

批准号：
8326195
负责人：
RUBINA A HEPTULLA
金额：
$ 39.85万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-08-31
项目状态：
已结题

项目摘要

Abstract 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.

抽象的靶向1型糖尿病（T1DM）中的高血糖可减少与糖尿病有关的并发症。使用胰岛素泵替换生理胰岛素是金治疗标准。这种方法依赖于患者从事血糖监测和胰岛素输送，尤其是用于进餐的大剂量。完全集成的闭合 - 环系统，由连续的葡萄糖监测和葡萄糖反应性胰岛素组成行政管理，并持有“智能胰岛素泵”的承诺。理想的封闭循环系统将消除对用户输入的需求。但是，目前闭环系统无法及时回应一顿饭，胰岛素单一疗法无法解决餐后高血糖。矛盾的是，美洲后高葡萄糖血症是与T1DM中餐后高血糖有关。胰高血糖素抑制剂，例如淀粉蛋白类似物，pramlintide和胰高血糖素像肽-1（GLP-1）模拟物，艾艾替尼，是被批准用于糖尿病的新代理商。淀粉蛋白是第二种β细胞激素与胰岛素共归化。餐后时期的淀粉蛋白会立即减少通过抑制胰高血糖素并延迟胃排空，餐后高血糖。这激素GLP-1的作用与链淀粉类似，并且在T1DM中也可能是有益的。这该提案的总体目标是将闭环系统技术与这些合并激素，这对于餐后葡萄糖稳态至关重要。在协议1中，我们将研究具有完全闭环设置的20个T1DM受试者。受试者将是随机的要么将pramlintide或a andenatide作为粉刷前推注。我们假设这是辅助pramlintide/Etenatide治疗量葡萄糖浓度会更好比单独的胰岛素。协议2将测试连续pramlintide和仅在闭环设置中与胰岛素中的胰岛素相对于胰岛素。 Medtronic是开发用于葡萄糖控制和Heptulla博士的闭环系统技术率先在T1DM中使用pramlintide和aTeNatide。这些协议将定义这些激素在闭环环境中的后葡萄糖稳态中的作用。此外，该试验有可能导致第二代闭环系统带有多激素的递送。这些协议将直接影响现有临床指南，甚至在商业供应之前也会改善血糖闭环系统。