Pediatric Type 1 diabetes: Intervention Trials With Glucagon Suppressors

描述(申请人提供)：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。胰升糖素抑制药，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，是被批准用于成人糖尿病的新药物。我们先前已经证明普拉林肽通过降低胰升糖素和延缓青少年T1 DM患者的胃排空来降低餐后高血糖。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。关于GLP-1在T1 DM中的使用，只有有限的信息可用。目前还没有研究确定普拉林肽和埃塞那肽对T1 DM患者的血糖控制是否有相似的效果。这项建议的总体目标是开发针对胰高血糖素的安全和有效的策略，并改善儿童T1 DM的血糖控制。方案1的具体目的是建立与我们为普拉林肽建立的降糖剂量等同的T1 DM患者的埃塞那肽降糖剂量。为此，15名T1 DM患者将被随机分成4个不同剂量的普鲁米松研究。此外，还将评估胰高血糖素抑制和胃排空延迟。在方案2中，我们假设埃塞那肽/普拉林肽在改善长期存在的T1 DM患者的血糖控制方面将比单独使用胰岛素更好。其次，对普拉林肽和埃塞那肽进行比较。40名确诊的T1 DM患者将接受为期3个月的单独胰岛素磨合，之后，受试者将在一项开放标签研究中被随机分配，接受为期6个月的每日两次普拉林肽或艾塞那肽与胰岛素的皮下注射。将在基线和治疗6个月时评估HbA1c、抗体状态、抗原特异性T细胞分析和对混合餐的C肽反应。如果血糖控制改善，自身免疫没有复发，那么将采用艾塞那肽方案3，以确定我们是否可以将这些发现推广到新发的T1 DM患者。在方案3中，我们假设艾塞那肽的应用将导致新发病的T1 DM患者持续或改善C-肽的产生。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，或仅接受胰岛素治疗，并将进行12个月的跟踪调查。对混合餐的C肽反应将被用来评估结果。如果这种疗法改善了血糖控制，那么它将为在所有新发的T1 DM患者中实施这种疗法铺平道路。然而，如果在使用艾塞那肽的方案2中发生自身免疫复发，那么我们将在方案3中测试普拉林肽，而不是艾塞那肽。埃塞那肽和/或普拉林肽的使用为我们提供了潜在的新工具来改善患有T1 DM的儿童和青少年的血糖控制，从而减少这种衰弱疾病的相关长期微血管并发症。

DESCRIPTION (provided by applicant): 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 T1DM 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 T1 DM. To address this hypothesis 80 subjects with new onset T1 DM 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 T1 DM 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. Uses of exenatide and/or pramlintide provide us with potentially new tools to improve glycemic control in children and adolescents with T1 DM and thus reduce associated long-term microvascular complications of this debilitating disease.