Pediatric Type 1 diabetes: Intervention Trials With Glucagon Suppressors

描述（由申请人提供）：1型糖尿病（T1DM）目前通过调节饮食中的碳水化合物和胰岛素来治疗。矛盾的餐后高胰高血糖素血症与T1DM患者餐后高血糖有关。胰高血糖素抑制剂，如胰高血糖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，是批准用于成人糖尿病患者的新药物。我们之前已经证明普兰林肽通过降低胰高血糖素和延迟T1DM青少年的胃排空来降低餐后高血糖。动物实验表明，GLP-1可增加β细胞质量，减少细胞凋亡。关于GLP-1在T1DM中使用的信息有限。没有研究报道确定普兰林肽和艾塞那肽对T1DM患者的血糖控制是否有相似的效果。本建议的总体目标是制定安全有效的策略，以胰高血糖素为目标，改善儿童T1DM的血糖控制。方案1的具体目的是建立与我们为普兰林肽建立的等效的艾塞那肽在T1DM中的降糖剂量。为此，15名T1DM患者将被随机分为4个研究，使用不同的普兰林肽剂量。胰高血糖素抑制和胃排空延迟也将被评估。在方案2中，我们假设艾塞那肽/普兰林肽在改善长期T1DM患者的血糖控制方面优于单独使用胰岛素。其次，将对普兰林肽和艾塞那肽进行比较。40名确诊的T1DM患者将接受3个月的胰岛素单独治疗，随后受试者将被随机分配到一项开放标签研究中，每天两次皮下给药普兰林肽或艾塞那肽联合胰岛素，为期6个月。HbA1C、抗体状态、抗原特异性t细胞测定和c肽对混合膳食的反应将在基线和治疗6个月时进行评估。如果血糖控制得到改善，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扩展到新发病的T1DM受试者。在方案3中，我们假设艾塞那肽的使用将导致新发T1型糖尿病患者持续或改善c肽的产生。为了验证这一假设，我们将招募80名新发T1型糖尿病患者，随机接受艾塞那肽和胰岛素治疗，或单独接受胰岛素治疗，并随访12个月。c肽对混合膳食的反应将用于评估结果。如果这种治疗能改善血糖控制，那么它将为在所有新发T1型糖尿病患者中实施这种治疗铺平道路。然而，如果在方案2中使用艾塞那肽发生自身免疫复发，那么我们将在方案3中测试普兰林肽，而不是艾塞那肽。使用艾塞那肽和/或普兰林肽为改善T1型糖尿病儿童和青少年的血糖控制提供了潜在的新工具，从而减少了这种使人衰弱的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.