Beta Cell Restoration through Fat Mitigation

描述(由申请人提供)：我们研究计划的长期目标是了解导致2型糖尿病(T2D)的进行性细胞性疾病的原因并开发治疗方法。我们之前的工作和其他人的研究提供了重要的证据，证明肥胖的新陈代谢效应会导致细胞衰竭。生活方式的改变和改变身体脂肪或其生物学的药物似乎减缓或阻止了一些人的p细胞退化，但不是大多数人。我们假设，在保留或恢复细胞功能方面，由胃束带引起的实质性体重减轻将比最好的可用药物吡格列酮更有效。我们建议进行一项双臂非盲法研究，以比较胃束带术和吡格列酮在24个月期间对患有T2D前期或轻度T2D的中度肥胖西班牙裔成年人的治疗效果。主要结果将是胰岛素抵抗的细胞代偿性改变，我们将在不同组之间进行比较。我们还将检查其他潜在的细胞健康标志物。二次分析将检查特定治疗效果的潜在介体，并寻找更一般的细胞修复或保存介体。主要焦点将放在与肥胖相关的调解人身上。我们还将研究空腹血糖作为细胞恢复或保存的潜在介体。在临床上，该项目将作为对胃带在肥胖症和细胞性疾病谱系中相对早期使用的概念的测试。从生物学上讲，这些结果将提供有关肥胖背景下细胞衰竭及其抑制或逆转的潜在媒介的关键信息。这些介体将指导对引起T2D的细胞性疾病进行更有效的治疗和监测。我们已经从Allergen那里获得了资助胃束带臂临床护理的协议，所以我们的方法对NIH来说是具有成本效益的。 我们带来了领域领先的专业知识--细胞生物学和人类保存。最终，我们相信我们可以为T2D领域以及将由该RFA组成的联盟做出重要的新贡献，以促进该领域的临床和生物学知识。 公共卫生相关性(由申请者提供)：该项目将比较两种主要的治疗方法，一种是外科(胃束带)，另一种是内科(吡格列酮)，以了解它们对患有糖尿病前期或轻度2型糖尿病的中度肥胖的拉美裔美国人的影响。这一结果将有助于开发更有效的治疗和预防2型糖尿病的方法，以及更好地监测治疗成功的方法。 注意：以下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总结声明正面页面上的数字分数之间存在任何差异，则应将数字分数视为小组讨论最终结果的最准确表示

DESCRIPTION (provided by applicant): The long-term objective of our research program is to understand causes of and develop treatments for the progressive ¿-cell disease that causes type 2 diabetes (T2D). Our prior work and research by others provides important evidence that metabolic effects of obesity cause ¿-cell failure. Lifestyle changes and medications that alter body fat or its biology appear to slow or stop p-cell deterioration in some people, but not most. We hypothesize that substantial weight loss induced by gastric banding will be more effective than the best available medication, pioglitazone, in preserving or restoring ¿-cell function. We propose a 2-arm, unblinded study to compare gastric banding to treatment with pioglitazone over a 24-month period in moderately obese Hispanic adults with pre- or mild T2D. The primary outcome will be change in ¿-cell compensation for insulin resistance, which we will compare between groups. We will also examine other potential markers of ¿-cell health. Secondary analyses will examine potential mediators of treatment-specific effects and look for more general mediators of ¿-cell restoration or preservation. The main focus will be on mediators related to obesity. We will also examine fasting glycemia as a potential mediator of ¿-cell restoration or preservation. Clinically, the project will serve as a test of concept for use of gasric banding relatively early in the spectrum of obesity and ¿-cell disease. Biologically, the results will provide crucial information on potential mediators of ¿-cell failure and its arrest or reversa in the context of obesity. Those mediators will guide the development of more effective treatment and monitoring for the ¿-cell disease that causes T2D. We have secured agreement from Allergen to fund clinical care in the gastric band arm, so our approach is cost-effective for NIH. We bring field-leading expertise in ¿-cell biology and preservation in humans. In the end, we believe we can make important new contributions to the field of T2D, as well as to the consortium that will be formed out of this RFA to advance clinical and biological knowledge in that field. PUBLIC HEALTH RELEVANCE (provided by applicant): This project is will compare two leading treatments, one surgical (gastric banding) and one medical (pioglitazone) for their impact on moderately obese Hispanic Americans with prediabetes or mild type 2 diabetes. The results will help to develop more effective approaches to treat and prevent type 2 diabetes and better ways to monitor the success of treatment. NOTE: The following critiques 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