Role of Oral vs Injectable Glucagon Suppressors

描述（由申请人提供）：在胰岛素缺乏的1型糖尿病（T1DM）患者中，人工胰腺（AP）闭环（CL），葡萄糖敏感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。胰高血糖素是一种α细胞激素，是低血糖时释放的一线反调节激素，可增加肝脏葡萄糖的产生，通常在餐后被抑制。在糖尿病中，除了胰岛素缺乏，还有胰高血糖素失调。餐后高胰高血糖素血症和高血糖，以及胰高血糖素对低血糖的反应未能增加，使得单胰岛素治疗AP困难，如果需要双重或三重激素输注，则更复杂。在过去的十年里，我们研究了各种胰高血糖素抑制剂，胰高血糖素，GLP-1和西格列汀来解决这个问题。我们已经证明，艾塞那肽是一种可注射的胰高血糖素样肽-1 （GLP-1）受体类似物，对降低CL患者餐后高血糖非常有效。目前，我们正在比较艾塞那肽和利拉鲁肽（另一种长效GLP-1类似物）在CL治疗中的疗效。我们提出了一种对抗高血糖和低血糖的新方法，通过引入辅助西格列汀，这是一种FDA批准的药物，每天服用一次。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起作用。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，以研究其对CL环境下的餐后高血糖和高胰高血糖素血症的影响。维格列汀（未获美国批准的DPP4抑制剂）在胰岛素诱导的低血糖反应中增加胰高血糖素。西格列汀的这种效果还有待检验。在方案2中，我们将比较艾塞那肽和西格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，我们将比较艾塞那肽和西格列汀在闭环系统中的作用，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

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.