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（由申请方提供）：靶向治疗1型糖尿病（T1 DM）高血糖可减少糖尿病相关并发症。使用胰岛素泵进行生理性胰岛素替代是治疗的金标准。该方法依赖于患者参与血糖监测和胰岛素输送，尤其是餐时推注。完全集成的闭环系统，包括连续葡萄糖监测和葡萄糖响应胰岛素管理，并持有承诺的“智能胰岛素泵。“理想的闭环系统将满足用户输入的需求。然而，目前的闭环系统无法及时响应进餐，胰岛素单一疗法无法解决餐后高血糖症。特别是，餐后高胰高血糖素血症与T1 DM患者的餐后高血糖症相关。胰高血糖素抑制剂，如胰淀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。胰淀素是与胰岛素共同分泌的第二种β细胞激素。胰淀素在餐后阶段通过抑制胰高血糖素和延迟胃排空来降低餐后即刻高血糖症。激素GLP-1与胰淀素具有相似的作用，也可能对T1 DM有益。该提案的总体目标是将闭环系统技术与这些激素合并，这些激素对餐后葡萄糖稳态至关重要。在方案1中，我们将在全闭环设置下研究20例T1 DM受试者。受试者将随机接受普兰林肽或艾塞那肽作为餐前推注。我们假设普兰林肽/艾塞那肽联合治疗餐后血糖浓度比单用胰岛素更好。方案2将测试在闭环环境中持续普兰林肽和胰岛素相对于胰岛素单药治疗的可行性。Medtronic是葡萄糖控制闭环系统技术开发的领导者，Heptulla博士率先在T1 DM中使用普兰林肽和艾塞那肽。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，这项试验有可能导致第二代闭环系统与多激素输送。这些协议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可接受性。 公共卫生关系：闭环系统为1型糖尿病患者提供了一种更好的方法来管理他们的疾病，通过连续监测葡萄糖和输送胰岛素，而无需患者干预。然而，该方法不能以最佳方式响应由于进餐引起的葡萄糖变化，导致高于期望的餐后葡萄糖波动。普兰林肽和艾塞那肽是膳食相关激素，在糖尿病中没有适当的调节;本提案测试了这些激素与闭环系统的使用，以解决膳食相关的高血糖。