Pediatric Type 1 diabetes: Intervention Trials With Glucagon Suppressors

1型糖尿病（T1 DM）目前通过调节饮食碳水化合物和胰岛素进行管理。 T1 DM患者餐后高胰高血糖素血症与餐后高血糖症相关。血糖素 抑制剂如胰淀素类似物普兰林肽和胰高血糖素样肽-1（GLP-1）类似物艾塞那肽， 是被批准用于成人糖尿病的新药物。我们之前已经证明普兰林肽可以降低 通过降低胰高血糖素和延迟胃排空来治疗青少年餐后高血糖症 T1DM。GLP-1在动物研究中已显示增加β细胞质量并减少细胞凋亡。只有有限 关于GLP-1在T1 DM中使用的信息可用。尚无研究报告确定普兰林肽是否 和艾塞那肽对T1 DM的血糖控制具有相似的作用。本提案的总体目标是发展 针对胰高血糖素和改善儿童T1 DM血糖控制的安全有效策略。具体 方案1的目的是确定艾塞那肽在T1 DM中的降糖剂量， 为普兰林肽建立。为此，15例T1 DM受试者将随机分配至4项研究， 普兰林肽剂量。还将评估胰高血糖素抑制和胃排空延迟。在协议2中，我们 假设艾塞那肽/普兰林肽在改善血糖控制方面优于单独胰岛素， 长期T1 DM将对普兰林肽和依塞那肽进行二次比较。四十 确诊的T1 DM受试者将接受3个月的胰岛素单药导入，之后受试者将 在一项开放标签研究中随机接受普兰林肽每日两次皮下给药或 艾塞那肽联合胰岛素治疗6个月。HbA 1C、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测定和C肽反应。如果 如果血糖控制改善，并且自身免疫性没有复发，则使用艾塞那肽的方案3将是 以确定我们是否可以将这些发现扩展到新发T1 DM受试者。在协议3中，我们 假设艾塞那肽给药将导致新发作患者持续或改善C肽产生 T1DM。为了解决这一假设，将招募80例新发T1 DM受试者，并随机接受 艾塞那肽和胰岛素，或单独使用胰岛素，并随访12个月。C肽对混合餐的反应将 用于评估结果。如果这种疗法能改善血糖控制， 所有新发T1 DM患者的治疗。然而，如果在方案2中发生自身免疫复发， 那么我们将在方案3中测试普兰林肽而不是艾塞那肽。使用exenetamine和/或 普兰林肽为我们提供了改善儿童和青少年血糖控制的潜在新工具， T1 DM，从而减少这种衰弱性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.