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）：针对 1 型糖尿病 (T1DM) 的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，尤其是餐丸注射。完全集成的闭环系统由连续血糖监测和葡萄糖反应性胰岛素管理组成，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响应进餐，并且胰岛素单一疗法无法解决餐后高血糖。矛盾的是，餐后高胰高血糖素血症与 T1DM 的餐后高血糖有关。胰高血糖素抑制剂，例如胰岛淀粉样多肽类似物、普兰林肽和胰高血糖素样肽-1 (GLP-1) 模拟物、艾塞那肽，是批准用于治疗糖尿病的新药。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迟胃排空来降低餐后立即高血糖。激素 GLP-1 具有与胰淀素类似的作用，也可能对 T1DM 有益。该提案的总体目标是将闭环系统技术与这些激素相结合，这对餐后血糖稳态至关重要。在方案 1 中，我们将在全闭环设置下研究 20 名 T1DM 受试者。受试者将被随机分配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/艾塞那肽辅助治疗的餐后血糖浓度会比单独使用胰岛素更好。方案 2 将测试在闭环环境中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 (Medtronic) 是血糖控制闭环系统技术开发领域的领导者，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，该试验有可能产生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，甚至在闭环系统商业化之前也将改善血糖。 公共健康相关性：闭环系统通过持续监测血糖和输送胰岛素，无需患者干预，为 1 型糖尿病患者提供了更好的疾病管理方法。然而，该方法无法以最佳方式响应膳食引起的血糖变化，导致餐后血糖波动高于预期。普兰林肽和艾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；该提案测试了这些激素与闭环系统的使用，以解决与膳食相关的高血糖问题。