Enhancement of Beta Cell Function with Pharmacologic and Sleep Apnea Treatment

描述(申请人提供)：预防2型糖尿病是一项关键且可实现的目标预防或延缓糖尿病前期患者发生T2 DM的干预措施侧重于通过改变生活方式、使用降胰岛素药物、 或者两者都有。胰岛素治疗的引入，例如GLP激动剂，使得确定是否可以通过保存或增强胰岛素分泌的策略获得类似或更好的结果。这项随机临床试验的总体目标是确定联合应用吡格列酮是否会增强服用利拉鲁肽所带来的预期的胰岛素分泌增加。吡格列酮是一种胰岛素增敏剂，将“减轻β细胞的负担”，并保护β细胞的功能。这一组合将与利拉鲁肽+安慰剂进行比较，以确定如果有的话，吡格列酮的作用是否与利拉鲁肽相加或协同作用。我们方法的一个独特方面是，只要适用，OSA的CPAP治疗将被纳入治疗范例，并将作为分析药物治疗反应的协变量。OSA是胰岛素抵抗的独立危险因素。所有参与者将在基线和治疗后26周进行评估：用改进的最小模型分析的75克5小时OGTT，用等糖葡萄糖输注来评估胰岛素的效果，用fsIVGTT来评估airG和SI，以及用分级葡萄糖输注来评估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病史的妇女，患有多囊卵巢综合征的妇女，以及45岁的超重和肥胖者。具体目标如下：1.确定26周的利拉鲁肽+吡格列酮治疗是否优于利拉鲁肽+安慰剂，以改善糖尿病前期或新发的T2 DM患者的胰岛素分泌。具体目标2：确定β细胞对两种不同的药物干预方式(单独使用利拉鲁肽和利拉鲁肽+吡格列酮)的反应性是否受阻塞性睡眠呼吸暂停综合征和非裔美国人种族/民族的影响。具体目标3：确定在没有药物治疗的情况下，CPAP治疗OSA是否保留或增强了β细胞功能，以及OSA对胰岛素分泌和作用的影响是否受RACE调节。具体目的4：确定26周的利拉鲁肽+吡格列酮在延长药物治疗对β细胞功能的耐受性方面是否优于利拉鲁肽+安慰剂。 公共卫生相关性(由申请人提供)：本申请中拟议的研究为评估和理解β细胞在糖尿病前期和T2 DM发病机制中的作用带来了一个新的维度。创新方面包括要测试的药物组合的选择；对葡萄糖耐量的主要成分(β细胞对口服和静脉注射葡萄糖挑战的反应、胰岛素敏感性和胰岛素效应)的详细同步评估；最后是对OSA作为菊糖分泌调节剂的关键评估，以及对易患T2 DM的患者的胰岛素作用的评估。 注意：下面的评论是由分配给此应用程序的评审员准备的。这些评注不一定反映审评人在小组讨论结束时的立场或小组的最后多数意见，尽管审评人被要求修改他们的批评意见，如果他们的立场在讨论期间发生变化。摘要说明的简历和其他开头部分是小组讨论最后结果的权威性表述。如果同行评审员的评论与本摘要说明页面上的数字分数之间存在任何差异，则数字分数应被视为最准确地代表小组讨论的最终结果。

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. PUBLIC HEALTH RELEVANCE (provided by applicant): The proposed studies in this application bring a new dimension to the evaluation and understanding of the role of the beta cell in the pathogenesis of prediabetes and T2DM. Innovative aspects include the choice of the drug combination to be tested; detailed simultaneous assessment of the main components of glucose tolerance (beta cell responsiveness to oral and intravenous glucose challenges, insulin sensitivity, and incretin effect); and lastly to the critical evaluation of OSA as a modifier of inulin secretion and insulin action among subjects predisposed to develop T2DM. NOTE: The critiques below were prepared by the reviewers assigned to this application. These commentaries may not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representations of the final outcome of group discussion. If there is any discrepancy between the peer reviewers' commentaries and the numerical score on the face page of this summary statement, the numerical score should be considered the most accurate representation of the final outcome of the group discussion.