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

• 批准号: 7994071
• 负责人: RUBINA A HEPTULLA
• 金额: $ 1.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-16 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994071
• 关键词: Address; Adolescent; Adult; Animals; Antibodies; Antigens; Apoptosis; Attenuated; Autoimmunity; Beta Cell; Biological Assay; C-Peptide; Child; Childhood; Diabetes Mellitus; Diabetic Angiopathies; Dietary Carbohydrates; Disease; Dose; Gastric Emptying; Gastroparesis; Glucagon; Glucose; Glycosylated hemoglobin A; Hemoglobin; Hyperglycemia; Hypoglycemia; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; New Agents; Newly Diagnosed; Outcome; Patients; Pramlintide; Production; Protocols documentation; Randomized; Recrudescences; Recruitment Activity; Reporting; Running; T-Lymphocyte; Testing; analog; exenatide; glucagon-like peptide 1; glycemic control; hyperglucagonemia; improved; insulin secretion; islet amyloid polypeptide; open label; response; subcutaneous; tool

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.

描述（由申请人提供）：目前，1 型糖尿病（T1DM）是通过调节饮食碳水化合物和胰岛素来控制的。反常的餐后高胰高血糖素血症与 T1DM 餐后高血糖有关。胰高血糖素抑制剂，例如胰岛淀粉样多肽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，普兰林肽通过降低 T1DM 青少年的胰高血糖素和延迟胃排空来降低餐后高血糖。动物研究显示 GLP-1 可以增加 β 细胞质量并减少细胞凋亡。有关 GLP-1 在 T1DM 中使用的信息有限。目前尚无研究确定普兰林肽和艾塞那肽对 T1DM 血糖控制是否具有类似作用的研究报道。该提案的总体目标是制定针对胰高血糖素并改善儿童 T1DM 血糖控制的安全有效的策略。方案 1 的具体目标是确定 T1DM 中艾塞那肽的降糖剂量，相当于我们为普兰林肽确定的剂量。为此，15 名 T1DM 受试者将被随机分配到 4 项研究中，使用不同的普兰林肽剂量。还将评估胰高血糖素抑制和胃排空延迟。在方案 2 中，我们假设艾塞那肽/普兰林肽在改善长期 T1DM 的血糖控制方面比单独使用胰岛素更好。其次将进行普兰林肽和艾塞那肽之间的比较。 40 名已确诊的 T1DM 受试者将接受为期 3 个月的单独胰岛素磨合，随后受试者将在一项开放标签研究中随机接受每天两次皮下注射的普兰林肽或艾塞那肽与胰岛素联合治疗，为期 6 个月。将在基线和 6 个月的治疗期间评估 HbA1C、抗体状态、抗原特异性 T 细胞测定和对混合膳食的 C 肽反应。如果血糖控制得到改善并且自身免疫没有复发，则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 T1DM 受试者。在方案 3 中，我们假设艾塞那肽给药将导致新发 T1 DM 中 C 肽的产生持续或改善。为了验证这一假设，将招募 80 名新发 T1 型糖尿病受试者，并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。对混合膳食的 C 肽反应将用于评估结果。如果这种疗法能改善血糖控制，那么它将为所有新发 T1 糖尿病患者实施这种治疗铺平道路。然而，如果在使用艾塞那肽的方案 2 中出现自身免疫复发，那么我们将在方案 3 中测试普兰林肽而不是艾塞那肽。艾塞那肽和/或普兰林肽的使用为我们提供了潜在的新工具，可以改善患有 T1 型糖尿病的儿童和青少年的血糖控制，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。