Optimizing Recovery and Preservation of Endogenous Insulin Secretion

描述（申请人提供）：前驱糖尿病和2型糖尿病发病机制的核心缺陷是-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，除了高强度的生活方式外，噻唑烷二酮类药物（TZDs）是最有效的。这两种干预措施都能提高胰岛素敏感性，并可能使细胞“休息”，从而改善其功能。然而，目前尚不清楚在积极干预期后对细胞功能的益处是否能保持。肠促胰岛素相关药物，包括胰高血糖素样肽-1受体激动剂（GLP-1RA），可改善胰岛功能，但其预防糖尿病和减缓其进展的能力尚不清楚。因此，我们建议在糖尿病前期和未用药的轻度2型糖尿病患者中进行可行性研究，以验证我们的假设，即胰岛素增敏剂和促肠促胰岛素模拟药物联合积极降糖将导致糖尿病

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.