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Pediatric Type 1 diabetes: Intervention Trials With Glucagon Suppressors

儿童 1 型糖尿病：胰高血糖素抑制剂的干预试验

基本信息

批准号：
8141775
负责人：
RUBINA A HEPTULLA
金额：
$ 6.22万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

项目摘要

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.

1 型糖尿病 (T1DM) 目前通过调节膳食碳水化合物和胰岛素进行治疗。反常的餐后高血糖素血症与 T1DM 餐后高血糖有关。胰高血糖素抑制剂，例如胰淀素类似物、普兰林肽和胰高血糖素样肽-1 (GLP-1) 类似物、艾塞那肽、是批准用于成人糖尿病患者的新药。我们之前已经证明普兰林肽可以减少通过减少胰高血糖素和延迟胃排空来治疗青少年餐后高血糖 T1DM。动物研究显示 GLP-1 可以增加 β 细胞质量并减少细胞凋亡。仅限有限现有有关 GLP-1 在 T1DM 中使用的信息。尚无研究报告确定普兰林肽是否和艾塞那肽对 T1DM 的血糖控制具有相似的作用。该提案的总体目标是发展针对胰高血糖素和改善儿童 T1DM 血糖控制的安全有效的策略。具体的方案 1 的目的是确定 T1 DM 中艾塞那肽的降糖剂量，相当于我们现有的剂量为普兰林肽建立。为此，15 名 T1DM 受试者将被随机分配到 4 项研究中，研究的内容各不相同普兰林肽剂量。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使用胰岛素长期存在的 T1DM。其次将进行普兰林肽和艾塞那肽之间的比较。四十已确诊的 T1DM 受试者将接受为期 3 个月的单独胰岛素磨合，随后受试者将接受在一项开放标签研究中随机接受每天两次皮下注射普兰林肽或艾塞那肽与胰岛素联用，为期 6 个月。 HbA1C、抗体状态、抗原特异性 T 细胞将在基线和治疗 6 个月时评估对混合膳食的检测和 C 肽反应。如果血糖控制得到改善并且自身免疫没有复发，那么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 T1DM 受试者。在协议3中，我们假设艾塞那肽给药将导致新发病时 C 肽产生持续或改善 T1DM。为了验证这一假设，将招募 80 名新发 T1DM 受试者并随机接受艾塞那肽联合胰岛素，或单独使用胰岛素，并将随访 12 个月。 C 肽对混合膳食的反应用于评估结果。如果这种疗法可以改善血糖控制，那么它将为实施这种疗法铺平道路对所有新发 T1DM 患者进行治疗。然而，如果方案 2 中出现自身免疫复发，使用艾塞那肽然后我们将在方案 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 T1DM，从而减少与这种使人衰弱的疾病相关的长期微血管并发症。