Beta Cell Restoration through Fat Mitigation

描述（由申请人提供）：我们研究项目的长期目标是了解导致2型糖尿病（T2D）的进行性β细胞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，证明肥胖的代谢影响会导致β细胞衰竭。生活方式的改变和改变体脂或其生物学特性的药物似乎可以减缓或阻止某些人的β细胞退化，但不是大多数人。我们假设胃束带引起的体重减轻在保存或恢复β细胞功能方面比现有的最佳药物吡格列酮更有效。我们提出了一项两组非盲法研究，比较胃束带与吡格列酮治疗在中度肥胖的西班牙成年人中24个月的前期或轻度T2D。主要结果将是胰岛素抵抗的β细胞代偿的变化，我们将在两组之间进行比较。我们还将研究β细胞健康的其他潜在标志。二次分析将检查治疗特异性效果的潜在介质，并寻找更一般的β细胞恢复或保存介质。重点将放在与肥胖有关的介质上。我们还将研究空腹血糖作为β细胞恢复或保存的潜在介质。在临床上，该项目将作为在肥胖和β细胞疾病谱系中相对早期使用胃束带的概念测试。从生物学上讲，该结果将为肥胖背景下β细胞衰竭及其抑制或逆转的潜在介质提供重要信息。这些介质将指导开发更有效的治疗和监测导致T2D的β细胞疾病。我们已获得Allergen的同意，为胃带臂的临床护理提供资金，因此我们的方法对NIH来说是具有成本效益的。

DESCRIPTION (provided by applicant): The long-term objective of our research program is to understand causes of and develop treatments for the progressive beta-cell disease that causes type 2 diabetes (T2D). Our prior work and research by others provides important evidence that metabolic effects of obesity cause beta-cell failure. Lifestyle changes and medications that alter body fat or its biology appear to slow or stop beta-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 beta-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 beta-cell compensation for insulin resistance, which we will compare between groups. We will also examine other potential markers of beta-cell health. Secondary analyses will examine potential mediators of treatment-specific effects and look for more general mediators of beta-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 beta-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 beta-cell disease. Biologically, the results will provide crucial information on potential mediators of beta-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 beta-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 beta-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.