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）：目前使用饮食中碳水化合物和胰岛素的调节来管理1型糖尿病（T1DM）。悖论后的后高葡萄糖血症与T1DM中的餐后高血糖有关。胰高血糖素抑制剂，例如氨基蛋白类似物，pramlintide和胰高血糖素（如肽-1（GLP-1）类似物），是艾鉴定的，是批准用于糖尿病成人的新药物。我们以前曾证明，pramlintide通过减少胰高血糖素并延迟T1DM青少年的胃排空来降低餐后高血糖。在动物研究中，GLP-1已显示可增加β细胞量并减少凋亡。只有在T1DM中使用GLP-1的有限信息。尚无据报道，确定pramlintide和Etenatide对T1DM中血糖控制的影响是否相似。该提案的总体目的是制定针对胰高血糖素的安全有效策略，并改善小儿T1DM的血糖控制。方案1的具体目的是在T1DM中建立降糖剂量的降温剂量，等同于我们为pramlintide建立的升温剂量。在这一结束时，具有T1DM的15名受试者将随机分为4个研究，并具有不同的pramlintide剂量。胰高血糖素抑制和胃排空的延迟也将评估。在协议2中，我们假设在长期以来在长期以来T1DM中改善血糖控制方面，艾鉴定/pramlintide将比单独的胰岛素更好。其次，将进行pramlintide和Etenatide之间的比较。在开放标记的研究中，将有40个已建立的T1DM受试者仅与胰岛素单独使用胰岛素磨合3个月，该受试者将随机分配每天两次对Pramlintide或Entenatide和胰岛素结合使用两次，持续6个月。 HBA1C，抗体状态，特异性T细胞测定和对混合餐的C肽反应将在基线和6个月的治疗中进行评估。如果血糖控制有所改善，并且自身免疫性没有复发性，则将进行具有艾替尼的方案3，以确定我们是否可以将这些发现扩展到新的发作T1DM受试者。在协议3中，我们假设艾替酰胺给药将导致新发作T1 DM的持续或改善C肽产生。为了解决这一假设，将招募并随机分配新的T1 DM的80名受试者，以接收埃纳代肽和胰岛素，或单独接受胰岛素，并将遵循12个月。 C肽对混合餐的反应将用于评估结果。如果这种疗法改善了血糖控制，则将为在所有新发行的T1 DM患者中建立这种治疗铺平道路。但是，如果自身免疫的重现在协议2中使用艾塞那肽使用，则我们将在协议3中测试pramlintide，而不是埃纳替肽。亚烯酰胺和/或pramlintide的用途为我们提供了潜在的新工具，以改善具有T1 DM的儿童和青少年的血糖控制，从而减少了这种令人衰弱的疾病的相关长期的长期微血管并发症。