Enhancement of Beta Cell Function with Pharmacologic and Sleep Apnea Treatment

描述（由申请人提供）：预防T2 DM是一个关键且可实现的目标。预防或延迟前驱糖尿病患者发生T2 DM的干预措施主要集中在通过改变生活方式、使用降胰岛素药物、 或两者肠促胰岛素疗法的引入，例如，GLP激动剂，使得有可能确定是否可以用保持或增强胰岛素分泌的策略实现相似或上级结果。本随机临床试验的总体目标是确定与吡格列酮（一种胰岛素增敏剂，可“减轻β细胞负担”并保护β细胞功能）联合给药是否会增强利拉鲁肽给药引起的预期胰岛素分泌增加。将该复方制剂与利拉鲁肽+安慰剂进行比较，以确定吡格列酮的作用（如有）是否与利拉鲁肽的作用具有相加或协同作用。我们的方法的一个独特之处在于，只要适用，CPAP治疗OSA（胰岛素抵抗的独立危险因素）将被纳入治疗范式，并将作为药物治疗反应分析的协变量。所有受试者将在基线和治疗后26周进行评估：通过改良的最小模型分析75 gm 5-h OGTT，异甘草酸葡萄糖输注以估计肠促胰岛素效应，fsIVGTT以估计AIRg和Si，分级葡萄糖输注以评估β细胞功能。我们将针对高发病率的个人 糖尿病前期和T2 DM：有T2 DM一级亲属的成年人、有GDM既往史的女性、PCOS女性以及年龄>45岁的超重和肥胖个体。具体目标如下：具体目标1。确定利拉鲁肽+吡格列酮治疗26周在改善前驱糖尿病或近期发作的T2 DM个体的胰岛素分泌方面是否上级利拉鲁肽+安慰剂。具体目标二：确定β细胞对两种不同药理学干预方式（利拉鲁肽单药和利拉鲁肽+吡格列酮）的反应性是否受OSA和非裔美国人人种/种族的调节。具体目标3：确定在不进行药物治疗的情况下，通过CPAP治疗OSA是否保留或增强β细胞功能，以及OSA对胰岛素分泌和作用的影响是否受种族调节。具体目标4：确定利拉鲁肽+吡格列酮26周在延长药物治疗对β细胞功能的持久性方面是否上级利拉鲁肽+安慰剂。

DESCRIPTION (provided by applicant): Prevention of T2DM is a critical and attainable goal Interventions to prevent or delay development of T2DM in those with prediabetes have focused on reducing insulin resistance via lifestyle modification, the use of insulin lowering medications, or both. The introduction of incretin therapies, e.g., GLP agonists, makes it possible to determine if similar or superior outcomes can be achieved with strategies to preserve or enhance insulin secretion. The overall goal of this randomized clinical trial is to determine whether the expected augmentation in insulin secretion imparted by administration of liraglutide will be enhanced by the co-administration of pioglitazone, an insulin sensitizer that will "unburden the beta cell" and preserve beta cell function. This combination will be compared to liraglutide+placebo to determine whether the effects of pioglitazone, if any, are additive to or synergistic with those of liraglutide. A unique aspect of our approach is that, whenever applicable, CPAP treatment of OSA, an independent risk factor for insulin resistance, will be incorporated into the treatment paradigm and will serve as a covariate in the analysis of the response to pharmacologic therapy. All participants will be assessed at baseline and 26 wks post-treatment with: a 75gm 5-h OGTT analyzed by the modified minimal model, an isoglycemic glucose infusion to estimate the incretin effect, a fsIVGTT to estimate AIRg and Si, and a graded glucose infusion to assess beta cell function. We will target individuals with high rates of prediabetes and T2DM: adults with a first-degree relative with T2DM, women with a prior history of GDM, women with PCOS, and overweight and obese individuals aged >45 yr. The following Specific Aims will be addressed: Specific Aim 1. To determine if 26 wks of treatment with liraglutide+pioglitazone is superior to liraglutide+placebo in improving insulin secretion in individuals with prediabetes or recent-onset T2DM. Specific Aim 2: To determine if beta cell responsiveness to two different modalities of pharmacologic intervention (liraglutide alone and liraglutide+pioglitazone) is modulated by the presence of OSA and by African-American race/ethnicity. Specific Aim 3: To determine if treatment of OSA by CPAP preserves or enhances beta cell function in the absence of pharmacological treatment and if the impact of OSA on insulin secretion and action is modulated by race. Specific Aim 4: To determine if 26 wks of liraglutide+ pioglitazone is superior to liraglutide+placebo in extending the durability of drug treatment on beta cell function.