Optimizing Recovery and Preservation of Endogenous Insulin Secretion

优化内源性胰岛素分泌的回收和保存

• 批准号: 8334506
• 负责人: Steven Emanuel Kahn
• 金额: $ 111.37万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334506
• 关键词: 2,4-thiazolidinedione; Address; Agonist; Beta Cell; Biological Markers; Biological Preservation; Cell physiology; Cells; Clinical Research; Clinical Trials; Critiques; Defect; Diabetes Mellitus; Disease; Disease remission; Double-Blind Method; Face; Failure; Fasting; Feasibility Studies; Functional disorder; Future; Glucose; Glycosylated hemoglobin A; Hyperglycemia; Hypoglycemia; Impaired fasting glycaemia; Individual; Insulin; Insulin Resistance; Intervention; Intravenous; Lead; Life Style; Measures; Natural History; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oral; Outcome; Pathogenesis; Patient Care; Patients; Pharmaceutical Preparations; Pioglitazone; Placebos; Positioning Attribute; Prediabetes syndrome; Published Comment; Randomized; Recovery; Rest; Risk; Sampling; Series; Testing; Thiazolidinediones; Withdrawal; Work; Writing; active method; adipokines; arm; base; blood glucose regulation; cohort; diabetic patient; effective intervention; effective therapy; fasting glucose; functional improvement; glucagon-like peptide; glucose metabolism; glucose tolerance; high risk; improved; inflammatory marker; insight; insulin secretion; insulin sensitivity; insulin sensitizing drugs; islet; liraglutide; mimetics; peer; prevent; receptor; repository; response; volunteer

DESCRIPTION (provided by applicant): A core defect in the pathogenesis of both prediabetes and type 2 diabetes is ¿-cell dysfunction, with insulin resistance and ¿-cell dysfunction also being prominent. Attempts to prevent type 2 diabetes and its progression have shown that aside from intensive lifestyle, the thiazolidinediones (TZDs) are most effective. Both these interventions improve insulin sensitivity and presumably "rest" the ¿-cell, thereby improving its function. However, it is not known whether the benefits on ¿-cell function are maintained beyond the active intervention period. Incretin-related medications, including glucagon-like peptide-1 receptor agonists (GLP-1RA), improve islet function, but their ability to prevent diabetes and slow its progression is unknown. We thus propose a feasibility study in subjects with prediabetes and drug naive, mild type 2 diabetes to address our hypothesis that aggressive glucose lowering with the combination of an insulin sensitizer and an incretin mimetic will lead to recovery of islet function that will be sustained off treatment. We will undertake a two-arm, double-blind study in which subjects with prediabetes and drug-naive, recent onset, mild type 2 diabetes (HbA1c <7%) are randomized to receive the combination of the TZD pioglitazone and the GLP-1RA liraglutide or matching placebo for 12 months, followed by a 12-month washout period. ¿-cell function, ¿-cell function, insulin sensitivity and glucose tolerance will be assesse using both intravenous and oral tests. The use of these tests will allow us to determine how well simpler measures of ¿-cell function, ¿-cell function and insulin sensitivity from an oral glucose tolerance test correlate to more sophisticated measures obtained from intravenous testing. We will also create a sample repository in order to measure biomarkers and determine whether they predict glucose metabolism at baseline and the response to therapy. These studies will provide important new insight into the ability of aggressive glucose lowering, achieved with the combination of a TZD and GLP-1 RA, to prevent the progressive loss of ¿-cell function in prediabetes and type 2 diabetes. Further, they will inform regarding the utility of simpler measures for assessing glucose metabolism in large scale clinical trials.

描述（通过应用程序提供）：糖尿病前和2型糖尿病的发病机理中的核心缺陷均为 - 细胞功能障碍，胰岛素抵抗和细胞功能障碍也很突出。预防2型糖尿病及其进展的尝试表明，除了密集的生活方式外，噻唑烷二酮（TZD）是最有效的。这两种干预措施都提高了胰岛素的敏感性，并且大概“休息”了 - 从而提高了其功能。但是，尚不清楚是否维持在主动干预期之后的细胞功能上的好处。肠降血糖素相关的药物，包括胰高血糖素样肽-1受体激动剂（GLP-1RA），改善了胰岛功能，但是它们预防糖尿病和减慢其进展的能力尚不清楚。因此，我们建议对具有预测和药物幼稚，轻度2型糖尿病的受试者进行一项可行性研究，以解决我们的假设，即侵袭性糖糖降低与胰岛素敏化剂的组合降低和模拟物的增加将导致 胰岛功能的恢复，将维持治疗。我们将进行一项两臂，双盲研究，其中具有前糖和药物，最近发作的，轻度的2型糖尿病（HBA1C <7％）的受试者被随机分配，以接收TZD Pioglitazone和GLP-1RA liraglutide或GLP-1RA Liraglutide或匹配的安慰剂或匹配的安慰剂，持续了12个月，持续了12个月，遵循12个月的时间。 - 细胞功能，�-细胞功能，胰岛素敏感性和葡萄糖耐受性将通过静脉注射和口服测试进行评估。这些测试的使用将使我们能够确定从口服葡萄糖耐受性测试与从静脉内测试获得的更复杂的测量相关的细胞功能，细胞功能和胰岛素敏感性的更简单测量。我们还将创建一个样品存储库，以测量生物标志物并确定它们是否预测基线时的葡萄糖代谢和对治疗的反应。这些研究将为降低侵袭性葡萄糖降低的能力（通过TZD和GLP -1 RA的结合实现）提供重要的新见解，以防止糖尿病前期和2型糖尿病的循环丧失 - 细胞功能的逐渐丧失。此外，他们将告知在大规模临床试验中评估葡萄糖代谢的更简单测量的实用性。