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: 9136525
• 负责人: RUBINA A HEPTULLA
• 金额: $ 1.08万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136525
• 关键词: Role; Oral; vs; Injectable; Glucagon

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）：人造胰腺（AP）闭环（CL），胰岛素缺乏1型糖尿病（T1DM）患者的葡萄糖敏感胰岛素递送（T1DM）有望恢复尤格糖症，从而减少与糖尿病有关的长期并发症。 AP应用的主要障碍是后质量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，可增加肝葡萄糖的产生，通常在野前时期受到抑制。在糖尿病中，除了胰岛素缺乏外，还有胰高血糖素失调。饮食后矛盾的高葡萄糖血症和高血糖症以及胰高血糖素对低血糖的响应量增加，如果需要进行双重或三重激素输注，胰岛素单药治疗或更复杂的AP治疗使AP治疗难以进行。在过去的十年中，我们已经研究了各种胰高血糖素抑制剂的淀粉纤维，GLP-1和西格列汀，以解决此问题。我们已经证明，像肽-1（GLP-1）受体类似物（如肽-1（GLP-1）受体类似物）在CL环境中降低餐后高血糖症非常有效。目前，我们正在将艾鉴化剂与Cl设置中的liraglutide（另一个长作用GLP-1模拟）进行比较。我们提出了一种新颖的方法，可以通过引入FDA认可的药物辅助性西格列汀来对抗高血糖症和低血糖，每天将其作为药丸给予一次。西他列汀通过抑制二肽基肽酶4（DPP4）的作用，该酶代谢GLP-1并增加内源性GLP-1。 GLP-1抑制了餐后高血糖。在协议1中，我们将测试2剂西他列汀，以研究其对CL环境中普兰党高血糖和高葡萄糖症的影响。维尔迪格列汀（DPP4抑制剂未获得批准）会增加胰岛素的响应，以响应胰岛素诱导的 - 糖血糖。西他列汀仍有待测试。在协议2中，我们将比较高胰岛素低血糖夹期间艾塞那肽与西塔氏菌对胰高血糖素分泌的影响。最后，在协议3中，我们将比较艾替尼与闭环系统中西他列汀的影响，以确定哪种模拟对患者最有益。此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症和低血糖的最简单方法。 Medtronic是用于葡萄糖控制和Heptulla博士开发闭环系统技术的领导者，通过使用胰高血糖素抑制剂的辅助治疗率先进行了T1DM的辅助处理。这些方案旨在了解糖尿病中胰高血糖素失调的发病机理和治疗。它们旨在简化治疗，并使用最佳的胰高血糖素抑制剂来调节AP。