Role of Oral vs Injectable Glucagon Suppressors

描述(申请人提供)：胰岛素缺乏型1型糖尿病(T1 DM)患者的人工胰腺(AP)闭环(CL)葡萄糖敏感型胰岛素输送有望恢复正常血糖，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。胰升糖素是一种α细胞激素，是一种第一线的反调节激素，在低血糖时释放，增加肝脏葡萄糖的产生，通常在餐后阶段被抑制。在糖尿病患者中，除了胰岛素缺乏外，还有胰升糖素调节失调。反常的高血糖和餐后高血糖，以及低血糖时不能增加胰升糖素，使得AP难以单用胰岛素治疗，如果需要双或三种激素输注，则更加复杂。在过去的十年里，我们研究了各种胰升糖素抑制剂的淀粉素、GLP-1和西格列汀来对抗这个问题。我们已经证明，埃塞那肽，一种可注射的胰高血糖素样肽-1(GLP-1)受体类似物，在CL环境下非常有效地降低餐后高血糖。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)。我们提出了一种新的方法，通过引入佐剂西格列汀来对抗高血糖和低血糖，西格列汀是FDA批准的一种药物，每天以药丸的形式给药一次。西格列汀通过抑制代谢GLP-1的二肽基肽酶4(DPP4)和增加内源性GLP-1来发挥作用。GLP-1抑制餐后高血糖。在方案1中，我们将测试两种剂量的西格列汀，以研究其在CL环境下对术后高血糖和高血糖的影响。维拉格列汀(DPP4抑制剂，未获美国批准)可在胰岛素诱导的低血糖时增加胰高血糖素。西格列汀的这种效果还有待测试。在方案2中，我们将比较埃塞那肽和西格列蒂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埃塞那肽和西格列汀的效果，以确定哪种类似物对患者最有利。这个应用程序的首要目标是找到最好的 和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。开发血糖控制闭环系统技术的领先者美敦力和赫普图拉博士开创了使用胰升糖素抑制剂辅助治疗T1 DM的先河。这些方案旨在了解糖尿病患者胰升糖素失调的发病机制和治疗方法。他们的目标是简化治疗，并使用最好的胰升糖素抑制剂来调节AP的血糖。

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.