Feasibility, Efficacy, and Mechanisms of Surgical vs Medical Diabetes Treatment

描述（由申请人提供）：Roux-en-Y胃旁路治疗（RYGB）可显著改善2型糖尿病（T2DM），其机制尚不清楚，而不仅仅是减轻体重。然而，由于缺乏随机临床试验（rct）， RYGB与非手术糖尿病护理相比的风险-收益比尚不清楚，特别是对于肥胖程度较轻的患者。适当的随机对照试验的障碍包括招募足够数量的知情患者的挑战，这些患者愿意随机选择手术或非手术方法，他们有资金来源进行干预，并且没有被强迫进入干预部门，以及纵向数据收集的操作问题和描述T2DM改善机制的指标的可用性。我们建议通过追求三个目标来解决这些障碍。首先，我们将确定一种新方法的可行性，从一个综合医疗保健系统的成员中生成一个随机队列，该系统涵盖了BMI为bb0 35 kg/m2的患者的RYGB，并愿意在BMI为30-35 kg/m2的患者中进行这项研究。我们将利用该网络的数据库来识别BMI为30-40 kg/m2的T2DM成年人。将对足够数量的患者（4,000-6,000）进行调查，以确定对糖尿病和肥胖症的药物治疗和手术治疗没有强烈偏好的患者。这部分患者将接触到我们开发并验证的一种新的、标准化的共享决策（SDM）工具（该领域唯一的此类工具），该工具可以帮助患者探索两种治疗方案的风险和益处，之后他们的“随机化意愿”将被评估。其次，一组在SDM过程后保持平衡的患者将随机接受RYGB或最先进的强化医疗/生活方式干预，包括饮食、运动和药物治疗糖尿病/肥胖，我们已经帮助开发并在之前的随机对照试验中进行了测试。这项可行性随机对照试验的目标是证明我们的新队列生成方案的效用，确定实现适当样本量所需的接近数量，评估被动和主动数据收集机制的可靠性，确定并发医疗保健利用率（HCU）测量分配的准确性，并确定最终全面试验执行和保留所需的资源。第三，我们将评估在未来的试验中纳入一组新的指标来阐明RYGB的抗糖尿病机制的有效性。在随机患者中，我们将验证RYGB改变先天和/或适应性免疫以改善葡萄糖稳态的假设。脂肪组织和胰岛中由巨噬细胞和T淋巴细胞驱动的慢性炎症在T2DM发病机制中起关键作用，我们假设RYGB与它促进的体重减轻不成比例地逆转了这些过程。我们将通过量化两个随机组在基线、干预后2周和体重减轻7%时脂肪组织活检中的细胞炎症、全身炎症和抗胰岛t细胞反应性来验证这一假设，然后将这些发现与葡萄糖稳态的变化联系起来。

DESCRIPTION (provided by applicant): Roux-en-Y gastric bypass (RYGB) dramatically ameliorates type 2 diabetes mellitus (T2DM), through poorly understood mechanisms beyond just weight loss. However, due to a paucity of randomized clinical trials (RCTs) the risk-benefit ratio of RYGB compared to non-surgical diabetes care is unknown, especially for patients with less severe obesity. Barriers to appropriate RCTs include challenges in recruiting sufficient numbers of informed patients who are willing to be randomized to surgical or non-surgical approaches, who have a funding source for either intervention, and who are not coerced into an intervention arm, as well as operational issues in longitudinal data gathering and the availability of metrics to delineate mechanisms of T2DM improvement. We propose to address these barriers by pursuing 3 objectives. First, we will determine the feasibility of a novel approach to generating a randomization cohort from among members of an integrated healthcare system that covers RYGB for patients with BMI >35 kg/m2 and is willing to do so among those with BMI 30-35 kg/m2 for this study. We will utilize the databases of this network to identify adults with T2DM and a BMI of 30-40 kg/m2. Sufficient numbers of these patients (4,000-6,000) will be surveyed to identify those without strong preferences regarding medical vs. surgical treatment of diabetes and obesity. This subset will be exposed to a novel, standardized shared-decision-making (SDM) tool that we have developed and validated (the only such instrument in the field), which helps patients explore the risks and benefits of both treatment options, after which their "willingness to randomize" will be assessed. Second, a cohort of patients who remain in equipoise after the SDM process will be randomized to receive RYGB or a state-of-the-art intensive medical/lifestyle intervention of diet, exercise, and pharmacotherapy for diabetes/obesity that we have helped develop and tested in prior RCTs. The goal of this feasibility RCT will be to demonstrate the utility of our novel cohort generation scheme, to determine the number needed to approach to accomplish appropriate sample sizes, to assess the reliability of passive and active data collection mechanisms, to determine the accuracy of assignment of concurrent healthcare utilization (HCU) measurements, and to determine the resources required for eventual full-scale trial execution and retention. Third, we will assess the usefulness of including a set of novel metrics to elucidate anti-diabetic mechanisms of RYGB in future trials. Among randomized patients, we will test the hypothesis that RYGB alters innate and/or adaptive immunity to improve glucose homeostasis. Chronic inflammation driven by macrophages and T lymphocytes in adipose tissue and islets plays key roles in T2DM pathogenesis, and we hypothesize that RYGB reverses these processes disproportionately to the weight loss it promotes. We will test this hypothesis by quantifying cellular inflammation in adipose-tissue biopsies, systemic inflammation, and anti-islet T-cell reactivity in both randomized groups at baseline, 2 weeks after intervention, and at 7% weight loss, then correlate these findings with changes in glucose homeostasis.