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。

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.