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）：人工胰腺（AP）闭环（CL）、葡萄糖敏感性胰岛素输送在胰岛素缺乏型1型糖尿病（T1 DM）患者中有望恢复正常，从而减少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，可增加肝脏葡萄糖生成，通常在餐后期间受到抑制。在糖尿病中，除了胰岛素缺乏之外，还有胰高血糖素失调。餐后胰高血糖素血症和餐后高血糖症以及胰高血糖素对低血糖症的反应未能增加，使得AP治疗难以使用胰岛素单药治疗，或者如果需要双重或三重激素输注则更复杂。在过去的十年中，我们研究了各种胰高血糖素抑制剂胰淀素，GLP-1和西格列汀来解决这个问题。我们已经证明，艾塞那肽（一种可注射的胰高血糖素样肽-1（GLP-1）受体类似物）在降低CL环境中的餐后高血糖症方面非常有效。目前，我们正在比较艾塞那肽与利拉鲁肽（另一种长效GLP-1类似物）在CL环境中的作用。我们提出了一种新的方法，通过引入辅助西格列汀来对抗高血糖和低血糖，西格列汀是一种FDA批准的药物，每天服用一次。西格列汀通过抑制二肽基肽酶4（DPP 4）（GLP-1代谢酶）和增加内源性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种剂量的西格列汀，以研究其对CL背景下的Prandal后高血糖症和高胰高血糖素血症的影响。维达利（未经美国批准的DPP 4抑制剂）增加胰高血糖素以应对胰岛素诱导的低血糖。西格列汀的这种作用仍有待检验。在方案2中，我们将比较艾塞那肽与西格列替对高胰岛素低血糖钳夹期间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与西格列汀的作用，以确定哪种类似物对患者最有益。这个应用程序的首要目标是找到最好的 最简单的方法来克服与糖尿病治疗相关的高血糖和低血糖。Medtronic是葡萄糖控制闭环系统技术开发的领导者，Heptulla博士率先使用胰高血糖素抑制剂对T1 DM进行连续治疗。这些方案旨在了解糖尿病中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中的葡萄糖。