Role of Oral vs Injectable Glucagon Suppressors

口服与注射胰高血糖素抑制剂的作用

• 批准号: 8642920
• 负责人: RUBINA A HEPTULLA
• 金额: $ 114.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642920
• 关键词: Address; Adjuvant; Adjuvant Analgesic; Algorithms; Alpha Cell; Area; Artificial Pancreas; Attenuated; Child; Complex; Complication; Data; Development; Devices; Diabetes Mellitus; Dipeptidyl Peptidases; Disease; Dose; Enzymes; FDA approved; Failure; Funding; Future; GLP-I receptor; Glucagon; Glucose; Goals; Health; Hepatic; Hormonal; Hormones; Hyperglycemia; Hypoglycemia; Infusion procedures; Injectable; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Laboratories; Lead; Methods; Oral; Oral cavity; Pathogenesis; Patient Noncompliance; Patients; Pharmaceutical Preparations; Physiological; Placebos; Protocols documentation; Pump; Role; System; Technology; Testing; Work; analog; base; blood glucose regulation; combat; cost; exenatide; glucagon-like peptide; glucagon-like peptide 1; glucose monitor; glucose production; hyperglucagonemia; improved; inhibitor/antagonist; islet amyloid polypeptide; liraglutide; novel strategies; pill; response; sugar

DESCRIPTION (provided by applicant): The Artificial Pancreas (AP) closed loop (CL), glucose-sensitive insulin delivery in patients with insulin deficient type 1 diabetes (T1DM) holds promise in restoring euglycemia and thus decreasing long-term complication related to diabetes. Major impediments to the AP application are post-prandial hyperglycemia and post-absorptive hypoglycemia. Glucagon, an alpha cell hormone is a first-line counter-regulatory hormone released during hypoglycemia increases hepatic glucose production and is normally suppressed in the post-prandial period. In diabetes, in addition to insulin deficiency there is glucagon dysregulation. Paradoxical hyperglucagonemia and hyperglycemia after a meal and failure of glucagon to increase in response to hypoglycemia make AP treatment difficult with insulin monotherapy or more complicated if there were dual or triple hormonal infusion required. For the last decade we have investigated various glucagon suppressors' amylin, GLP-1 and sitagliptin to combat this problem. We have demonstrated that exenatide, an injectable glucagon like peptide-1 (GLP-1) receptor analog is very effective in reducing post-prandial hyperglycemia in the CL setting. Currently we are comparing exenatide to liraglutide (another long acting GLP-1 analog) in CL setting. We propose a novel approach to combating both hyper and hypoglycemia by introducing adjuvant sitagliptin, an FDA approved drug, which is given once daily as a pill. Sitagliptin acts by inhibiting dipeptidyl peptidase 4 (DPP4) the enzyme that metabolizes GLP-1 and increasing endogenous GLP-1. GLP-1 suppresses post-prandial hyperglycemia. In protocol 1, we will test 2 doses of sitagliptin to study its effect on post-prandal hyperglycemia and hyperglucagonemia in the CL setting. Vildagliptin (DPP4 inhibitor not US approved) increases glucagon in response to insulin- induced-hypoglycemia. Sitagliptin remains to be tested for this effect. In protocol 2, we will compare the effect of exenatide vs. sitaglipti on glucagon secretion during a hyperinsulinemic hypoglycemic clamp. Lastly, in protocol 3, we will compare the effects of exenatide to sitagliptin in the closed loop system to determine which analog is most beneficial to patients. The overarching goal of this application is to find the best and simplest way to overcome hyper and hypoglycemia associated with the treatment of diabetes. Medtronic, a leader in the development of closed-loop system technology for glucose control and Dr. Heptulla have pioneered adjunctive treatment of T1DM with the use of glucagon suppressors. These protocols aim to understand the pathogenesis and treatment of glucagon dysregulation in diabetes. They aim to simplify treatment and use the best glucagon suppressor for glucose regulation in AP.

描述（由申请人提供）：人工胰腺（AP）闭环（CL）、葡萄糖敏感型胰岛素输送给胰岛素缺乏型 1 型糖尿病（T1DM）患者有望恢复血糖正常，从而减少与糖尿病相关的长期并发症。 AP应用的主要障碍是餐后高血糖和吸收后低血糖。胰高血糖素是一种α细胞激素，是低血糖期间释放的一线反调节激素，会增加肝葡萄糖的产生，通常在餐后受到抑制。在糖尿病中，除了胰岛素缺乏之外，还存在胰高血糖素失调。反常的高胰高血糖素血症和餐后高血糖以及胰高血糖素不能响应低血糖而增加，使得胰岛素单一疗法难以进行 AP 治疗，如果需要双重或三重激素输注，则情况会变得更加复杂。在过去的十年中，我们研究了各种胰高血糖素抑制剂胰岛淀粉样多肽、GLP-1 和西格列汀来解决这个问题。我们已经证明，艾塞那肽是一种可注射的胰高血糖素样肽 1 (GLP-1) 受体类似物，对于降低 CL 环境中的餐后高血糖非常有效。目前，我们正在 CL 环境中比较艾塞那肽和利拉鲁肽（另一种长效 GLP-1 类似物）。我们提出了一种对抗高血糖和低血糖的新方法，即引入辅助西他列汀，这是一种 FDA 批准的药物，每天一次作为药丸服用。西格列汀通过抑制二肽基肽酶 4 (DPP4)（代谢 GLP-1 的酶）并增加内源性 GLP-1 发挥作用。 GLP-1 抑制餐后高血糖。在方案 1 中，我们将测试 2 剂西他列汀，以研究其在 CL 环境中对餐后高血糖和高胰高血糖素血症的影响。维格列汀（DPP4 抑制剂未经美国批准）可增加胰高血糖素以应对胰岛素引起的低血糖。西格列汀的这种作用仍有待测试。在方案 2 中，我们将比较艾塞那肽与西他列提在高胰岛素低血糖钳夹期间对胰高血糖素分泌的影响。最后，在方案3中，我们将在闭环系统中比较艾塞那肽和西格列汀的效果，以确定哪种类似物对患者最有益。该应用程序的总体目标是找到最好的 克服与糖尿病治疗相关的高血糖和低血糖的最简单方法。美敦力 (Medtronic) 是血糖控制闭环系统技术开发领域的领导者，Heptulla 博士开创了使用胰高血糖素抑制剂辅助治疗 T1DM 的先河。这些方案旨在了解糖尿病胰高血糖素失调的发病机制和治疗。他们的目标是简化治疗并使用最好的胰高血糖素抑制剂来调节 AP 的血糖。