Enhancement of Beta Cell Function with Pharmacologic and Sleep Apnea Treatment

通过药物和睡眠呼吸暂停治疗增强 β 细胞功能

• 批准号: 8247929
• 负责人: DAVID A EHRMANN
• 金额: $ 70.97万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247929
• 关键词: Accounting; Address; Adult; Affect; African American; Aftercare; Agonist; American; Behavior Therapy; Beta Cell; Biological Preservation; Body mass index; Cell physiology; Centers for Disease Control and Prevention (U.S.); Clinical Trials; Comorbidity; Continuous Positive Airway Pressure; Critiques; Development; Diabetes Mellitus; Diagnosis; Dimensions; Drug Combinations; Epidemic; Ethnic Origin; Evaluation; Face; First Degree Relative; Geographic Locations; Gestational Diabetes; Glucose; Glucose Intolerance; Goals; Individual; Infusion procedures; Insulin; Insulin Resistance; Intervention; Intravenous; Inulin; Laboratories; Life Style; Modality; Modeling; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; OGTT; Obesity; Obstructive Sleep Apnea; Oral; Outcome; Overweight; Participant; Pathogenesis; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Pioglitazone; Placebos; Play; Polycystic Ovary Syndrome; Population; Positioning Attribute; Prediabetes syndrome; Prevalence; Prevention; Published Comment; Race; Randomized Clinical Trials; Recording of previous events; Relative (related person); Risk Factors; Role; Sampling; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Staging; Structure of beta Cell of islet; System; Testing; Wireless Technology; Woman; aged; base; clinical practice; demographics; design; disorder prevention; early onset; experience; glucagon like peptide; glucagon-like peptide; glucose tolerance; improved; innovation; insulin secretion; insulin sensitivity; insulin sensitizing drugs; intravenous glucose tolerance test; liraglutide; peer; prevent; response; treatment response

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.

描述（由申请人提供）：预防T2DM是一种至关重要且可实现的目标干预措施，以防止或延迟患有糖尿病前期T2DM的开发，重点是通过修改生活方式，使用胰岛素降低药物，降低胰岛素的药物，降低胰岛素的耐药性， 或两者兼而有之。引入肠降血糖素疗法，例如GLP激动剂，可以通过保留或增强胰岛素分泌的策略来确定是否可以实现相似或卓越的结果。这项随机临床试验的总体目标是确定通过给予利拉格鲁肽施加的胰岛素分泌中的预期增强是否会通过吡格列酮的共同给药来增强，这是一种胰岛素敏化剂，胰岛素敏化剂将“取消β细胞”并保存beta beta细胞功能。这种组合将与利拉卢皮德+安慰剂进行比较，以确定吡格列酮（如果有的话）的影响是否与利拉格鲁肽的添加剂或协同作用。我们方法的一个独特方面是，每当适用的CPAP治疗OSA（胰岛素抵抗的独立危险因素）时，将纳入治疗范式中，并将作为对药理治疗反应的分析。所有参与者将在基线和26周进行处理后进行：75gm 5-H OGTT通过修改后的最小模型分析，是一种估算肠血糖蛋白效应的异形血糖葡萄糖输注，fSIVGTT，用于估计AIRG和SI的FSIVGTT，并估算了Glated Glucose Influpifus Infusion，以及评估Beta Celba Cell Funcorm。我们将针对高率的个人 糖尿病前和T2DM：具有T2DM一级亲戚的成年人，具有GDM史的妇女，PCOS的妇女，超重和肥胖的个体> 45岁。将解决以下特定目标：具体目标1。确定用liraglutide+pioglitazone的26周治疗在改善糖尿病前期或最近发作T2DM的个体的胰岛素分泌方面优于liraglutide+安慰剂。具体目的2：确定β细胞对药理干预措施（单独的Liraglutide和Liraglutide+Pioglitazone）的β细胞响应是否通过OSA和非裔美国人种族/种族的存在调节。特定目的3：确定在没有药理治疗的情况下通过CPAP蛋白保护或增强β细胞功能的OSA处理，以及OSA对胰岛素分泌和作用的影响是否通过种族调节。具体目标4：确定在延长β细胞功能上药物治疗的耐用性时，要确定26周的Liraglutide+ Pioglitazone是否优于Liraglutide+安慰剂。 公共卫生相关性（由申请人提供）：本申请中的拟议研究为评估和理解β细胞在糖尿病前和T2DM发病机理中的作用带来了新的维度。创新的方面包括选择要测试的药物组合；详细评估葡萄糖耐量的主要成分（对口服和静脉葡萄糖挑战，胰岛素敏感性以及肠肠素效应的β细胞反应性）的详细评估；最后，将OSA作为易蛋白分泌和胰岛素作用的修饰者进行了批判性评估，这些受试者易于发展T2DM。 注意：下面的批评是由分配给本申请的审阅者准备的。这些评论可能不一定反映在小组讨论结束时审阅者的立场或小组的最终多数意见，尽管要求审稿人在讨论期间的立场是否发生了变化，以修改其批评。摘要声明的简历和其他初始部分是小组讨论最终结果的权威表示。如果同行评审者的评论与本摘要声明面对面的数值分数之间存在任何差异，则应将数值分数视为小组讨论最终结果的最准确表示。