Novel Glucagon Modulators and the Closed Loop System

新型胰高血糖素调节剂和闭环系统

• 批准号: 7791091
• 负责人: RUBINA A HEPTULLA
• 金额: $ 35.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791091
• 关键词: Address; Area Under Curve; Beta Cell; Blood Glucose; Bolus Infusion; Clinical; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Disease; Gastroparesis; Generations; Glucagon; Glucose; Goals; Gold; Guidelines; Hormones; Hyperglycemia; Infusion procedures; Insulin; Insulin Infusion Systems; Insulin-Dependent Diabetes Mellitus; Intervention; Lead; Methods; New Agents; Patients; Physiological; Postprandial Period; Pramlintide; Protocols documentation; Randomized; Role; System; Technology; Testing; analog; blood glucose regulation; exenatide; glucagon-like peptide 1; glucose monitor; hyperglucagonemia; improved; islet amyloid polypeptide; mimetics; novel; public health relevance; standard care

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.

描述（由申请人提供）：靶向1型糖尿病（T1DM）中的高血糖可减少与糖尿病相关的并发症。使用胰岛素泵替代生理胰岛素是治疗的金标准。这种方法依赖于患者参与血糖监测和胰岛素输送，尤其是用于膳食大力。完全集成的闭环系统由连续的葡萄糖监测和葡萄糖反应性胰岛素给药组成，并持有“智能胰岛素泵”的承诺。理想的闭环系统将消除对用户输入的需求。但是，目前，闭环系统无法及时反应餐，胰岛素单药治疗无法解决餐后高血糖。矛盾的是，美洲后高葡萄糖血症与餐后高血糖有关T1DM。胰高血糖素抑制剂，例如淀粉蛋白类似物，pramlintide和胰高血糖素（如肽-1（GLP-1）模拟物，艾艾烯肽）是批准用于糖尿病的新药物。淀粉蛋白是与胰岛素共分泌的第二种β细胞激素。餐后期间的淀粉蛋白通过抑制胰高血糖素并延迟胃排空来降低餐后高血糖。激素GLP-1与淀粉蛋白具有相似的作用，并且在T1DM中也可能是有益的。该提案的总体目标是将闭环系统技术与这些激素合并，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。受试者将被随机地作为粉刷前的大注接受pramlintide或aceNatide。我们假设辅助性定头/大烯肽治疗比单独的胰岛素更好。协议2，将在闭环设置中与胰岛素相对于胰岛素连续pramlintide和胰岛素的可行性。 Medtronic是用于用于葡萄糖控制的闭环系统技术开发的领导者，Heptulla博士率先在T1DM中使用了Pramlintide和Etenatide。这些方案将定义这些激素在闭环环境中餐后葡萄糖稳态中的作用。此外，该试验有可能导致具有多激素递送的第二代闭环系统。这些方案将直接影响现有的临床准则，即使在闭环系统的商业供应之前，也将改善血糖。 公共卫生相关性：闭环系统为患有1型糖尿病的患者提供了一种通过持续监测葡萄糖和胰岛素输送而无需患者干预来控制其疾病的更好方法。但是，该方法无法以最佳方式响应葡萄糖的变化，从而导致高于所需的光葡萄糖偏移。 pramlintide和Etenatide是与饮食相关的激素，在糖尿病中不适当调节。该提案测试了这些激素与封闭环系统的使用，以解决与进餐有关的高血糖。