Optimizing Recovery and Preservation of Endogenous Insulin Secretion

描述(申请人提供)：糖尿病前期和2型糖尿病发病机制中的一个核心缺陷是细胞功能障碍，胰岛素抵抗和细胞功能障碍也是突出的。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。这两种干预措施都能改善胰岛素敏感性，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之后，对细胞功能的好处是否会保持下去。胰岛素相关药物，包括胰升糖素样肽-1受体激动剂(GLP-1RA)，可以改善胰岛功能，但它们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药物未服用的轻度2型糖尿病患者中进行一项可行性研究，以解决我们的假设，即积极的降糖与胰岛素增敏剂和胰岛素类似物的结合将导致 胰岛功能的恢复将在治疗结束后维持。我们将进行一项双臂双盲研究，将糖尿病前期和新近发病的药物未服用的轻度2型糖尿病(HbA1c；lt；7%)的受试者随机分成两组，分别接受TZD吡格列酮和GLP-1RA利拉鲁肽或匹配的安慰剂的联合治疗12个月，然后是12个月的洗脱期。将使用静脉和口服测试来评估细胞功能、细胞功能、胰岛素敏感性和葡萄糖耐量。使用这些测试将使我们能够确定从口服葡萄糖耐量测试中获得的细胞功能、细胞功能和胰岛素敏感性的简单测量与通过静脉测试获得的更复杂的测量之间的相关性有多好。我们还将创建一个样本库，以测量生物标记物，并确定它们是否可以预测基线时的葡萄糖代谢和治疗反应。这些研究将为TZD和GLP-1 RA联合使用以防止糖尿病前期和2型糖尿病患者细胞功能进行性丧失的能力提供重要的新见解。此外，他们还将介绍在大规模临床试验中使用更简单的方法评估葡萄糖代谢的有效性。

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.