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: 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
• 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
• 来源: https://reporter.nih.gov/project-details/8326195
• 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; abstracting; analog; blood glucose regulation; exenatide; glucagon-like peptide; glucagon-like peptide 1; glucose monitor; hyperglucagonemia; improved; islet amyloid polypeptide; mimetics; novel; standard care

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.

摘要 针对1型糖尿病(T1 DM)的高血糖可减少糖尿病相关疾病 并发症。使用胰岛素泵的生理性胰岛素替代是黄金 治疗标准。这种方法依赖于患者的血糖水平。 监测和胰岛素输送，特别是进餐时。完全集成的封闭式 循环系统，由连续血糖监测和血糖反应胰岛素组成 管理，并持有“智能胰岛素泵”的承诺。理想的闭合- 循环系统将不再需要用户输入。然而，目前的闭环 系统不能及时对食物做出反应，胰岛素单一疗法也不能 解决餐后高血糖问题。矛盾的是，餐后高血糖素血症 与T1 DM患者餐后高血糖相关。胰高血糖素抑制物，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， 是否有新的药物被批准用于治疗糖尿病。胰淀素是第二种β细胞激素， 与胰岛素共同分泌。餐后期间的胰淀素会立即减少 通过抑制胰高血糖素和延迟胃排空而导致餐后高血糖。这个 激素GLP-1具有与胰淀素类似的作用，也可能对T1 DM有益。这个 该提案的总体目标是将闭环系统技术与这些 荷尔蒙，这是餐后血糖平衡的关键。在协议1中，我们将 对20名T1 DM受试者进行全闭环实验研究。受试者将被随机化 或者接受普拉林肽或艾塞那肽作为餐前丸剂。我们假设- 辅助性普拉林肽/埃塞那肽治疗可改善血糖水平 而不只是胰岛素。议定书2，将测试连续普拉林肽和 在闭环设置中的胰岛素与单独使用胰岛素相比。美敦力是世界上 开发血糖控制的闭环系统技术，赫普图拉博士 率先在T1 DM中使用普拉林肽和埃塞那肽。这些协议将定义 这些激素在闭环环境下餐后血糖动态平衡中的作用。 此外，这项试验有可能导致第二代闭环系统 使用多种荷尔蒙注射。这些协议将对现有的 临床指南，并将改善血糖，甚至在商业上市之前 闭环系统。

项目成果

Role of glucagon-like peptide-1 analogue versus amylin as an adjuvant therapy in type 1 diabetes in a closed loop setting with ePID algorithm.

• DOI: 10.1177/1932296814542153
• 发表时间: 2014-09-01
• 期刊: Journal of diabetes science and technology
• 影响因子: 5
• 作者: Renukuntla, Venkat Sasidhar;Ramchandani, Neesha;Heptulla, Rubina A
• 通讯作者: Heptulla, Rubina A