Pediatric Type 1 diabetes: Intervention Trials With Glucagon Suppressors

1型糖尿病(T1 DM)目前是通过调节饮食碳水化合物和胰岛素来管理的。 矛盾的餐后高血糖与T1 DM的餐后高血糖相关。胰高血糖素 抑制物，如胰淀素类似物、普拉林肽和胰升糖素样肽-1(GLP-1)类似物，埃塞那肽， 新药物是否被批准用于成人糖尿病患者。我们之前已经证明了普拉林肽可以降低 降低胰高血糖素和延缓胃排空对青少年餐后高血糖的影响 T1 DM。GLP-1在动物研究中已被证明可以增加β细胞质量，减少细胞凋亡。仅限 有关GLP-1在T1 DM中的使用信息。目前还没有研究报告确定普拉林肽是否 与艾塞那肽对T1 DM患者的血糖控制作用相似。这项提议的总体目标是发展 针对胰高血糖素和改善儿童T1 DM血糖控制的安全有效的策略。具体的 方案1的目的是建立与我们现有的降糖剂量等同的T1 DM患者的降糖剂量 为普拉林德设立的。为此，15名患有T1 DM的受试者将被随机分成4个不同的研究 普拉林德剂量。此外，还将评估胰高血糖素抑制和胃排空延迟。在议定书2中，我们 假设埃塞那肽/普拉林肽在改善血糖控制方面比单独使用胰岛素更好。 长期存在的T1 DM。其次，对普拉林肽和埃塞那肽进行比较。四十 确诊的T1 DM患者将进行为期3个月的单独胰岛素磨合，随后受试者将 在一项开放标记的研究中随机接受每日两次的普拉林肽皮下注射或 艾塞那肽联合胰岛素治疗6个月。HbA1c，抗体状态，抗原特异性T细胞 将在基线和治疗6个月时评估对混合餐的分析和C-肽反应。如果 血糖控制改善，自身免疫没有复发，那么方案3将使用埃塞那肽 以确定我们是否可以将这些发现扩展到新发的T1 DM患者。在协议3中，我们 假设在新的发病中给予埃塞那肽将导致持续或改善C-肽的产生 T1 DM。为了解决这一假设，80名新发的T1 DM患者将被招募并随机接受 艾塞那肽和胰岛素，或单用胰岛素，并将被跟踪12个月。C-肽对混合餐的反应将 被用来评估结果。如果这种疗法改善了血糖控制，那么它将为建立这种 对所有新发的T1糖尿病患者进行治疗。然而，如果自体免疫复发发生在具有 使用艾塞那肽，然后我们将在方案3中测试普拉林肽，而不是艾塞那肽。使用艾塞那肽和/或 普拉林肽为我们提供了潜在的新工具来改善儿童和青少年的血糖控制 从而减少这种使人衰弱的疾病的相关长期微血管并发症。

Type 1 diabetes mellitus (T1DM) is currently managed using modulation of dietary carbohydrates and insulin. Paradoxical post-meal hyperglucagonemia is associated with post-prandial hyperglycemia in T1DM. Glucagon suppressors such as the amylin analog, pramlintide, and the glucagon like peptide-1 (GLP-1) analog, exenatide, are new agents approved for use in adults with diabetes. We have previously demonstrated pramlintide reduces post-prandial hyperglycemia by decreasing glucagon and delaying gastric emptying in adolescents with T1DM. GLP-1 in animal studies has been shown to increase beta cell mass and decrease apoptosis. Only limited information is available on the use of GLP-1 in T1DM. No studies have been reported to determine if pramlintide and exenatide have similar effects on glycemic control in T1DM. The overall aim of this proposal is to develop safe and effective strategies targeting glucagon and improving glycemic control in pediatric T1DM. The specific aim of Protocol 1 is to establish a glucose-lowering dose of exenatide in T1 DM equivalent to that which we have established for pramlintide. To this end 15 subjects with T1DM will be randomized to 4 studies with varying pramlintide doses. Glucagon suppression and delay in gastric emptying will also be assessed. In protocol 2, we hypothesize that exenatide/pramlintide will be better than insulin alone in improving glycemic control in longstanding T1DM. Secondarily comparisons between pramlintide and exenatide will be undertaken. Forty established T1DM subjects will have a run-in with insulin alone for 3 months following which subjects will be randomized in an open-labeled study to receive either twice daily subcutaneous administration of pramlintide or exenatide in conjunction with insulin for a period of 6 months. HbA1C, antibody status, antigen specific T-cell assays and C-peptide response to a mixed meal will be assessed at baseline and with 6 months of treatment. If glycemic control improves and there is no recrudescence in autoimmunity then protocol 3 with exenatide will be undertaken to determine if we could extend these findings to new onset T1DM subjects. In protocol 3, we hypothesize that exenatide administration will result in sustained or improved C-peptide production in new onset T1DM. To address this hypothesis 80 subjects with new onset T1DM will be recruited and randomized to receive exenatide and insulin, or insulin alone and will be followed for 12 months. C-peptide response to a mixed meal will be used to assess outcomes. If this therapy improves glycemic control then it will pave the way for instituting this treatment in all new-onset T1DM patients. However, if recrudescence of autoimmunity occurs in protocol 2 with exenatide use then we will test pramlintide in protocol 3 as opposed to exenatide. Use of exenatide and/or pramlintide provide us with potentially new tools to improve glycemic control in children and adolescents with T1DM and thus reduce associated long-term microvascular complications of this debilitating disease.