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

描述（由申请人提供）：Roux-en-Y胃旁路术（RYGB）通过除体重减轻外尚不清楚的机制显著改善2型糖尿病（T2 DM）。然而，由于缺乏随机临床试验（RCTs），RYGB与非手术糖尿病护理相比的风险效益比尚不清楚，特别是对于不太严重的肥胖患者。适当RCT的障碍包括招募足够数量的知情患者的挑战，这些患者愿意随机分配到手术或非手术方法，有任何一种干预的资金来源，并且没有被强迫进入干预组，以及纵向数据收集的操作问题和描述T2 DM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，该方法从综合医疗保健系统的成员中产生随机队列，该系统涵盖BMI >35 kg/m2的患者的RYGB，并且愿意在BMI 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识别BMI为30-40 kg/m2的T2 DM成人。将对足够数量的这些患者（4，000 - 6，000）进行调查，以确定那些对糖尿病和肥胖症的药物与手术治疗没有强烈偏好的患者。该子集将暴露于我们开发并验证的新型标准化共享决策（SDM）工具（该领域唯一的此类工具），该工具帮助患者探索两种治疗方案的风险和益处，之后将评估他们的“随机化意愿”。其次，在SDM过程后保持平衡的患者队列将随机接受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RCT中进行了测试。本可行性RCT的目标是证明我们的新型队列生成方案的实用性，确定达到适当样本量所需的数量，评估被动和主动数据收集机制的可靠性，确定同时医疗保健利用（HCU）测量分配的准确性，并确定最终全面审判的执行和保留所需的资源。第三，我们将评估在未来的试验中包括一组新的指标来阐明RYGB的抗糖尿病机制的有用性。在随机化患者中，我们将检验RYGB改变先天和/或适应性免疫以改善葡萄糖稳态的假设。 由脂肪组织和胰岛中的巨噬细胞和T淋巴细胞驱动的慢性炎症在T2 DM发病机制中起关键作用，我们假设RYGB逆转这些过程与其促进的体重减轻不成比例。我们将通过量化两个随机分组在基线、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细胞反应性来检验这一假设，然后将这些发现与葡萄糖稳态的变化相关联。 公共卫生相关性：肥胖症和2型糖尿病（T2 DM）的流行不断升级，是全球发病率和死亡率的最重要因素之一。Roux-en-Y胃旁路术（RYGB）手术导致体重显著减轻，并通过体重减轻以外的机制显着改善T2 DM，但由于缺乏适当的随机试验，其在糖尿病管理中的作用及其与体重无关的抗糖尿病作用的性质尚未得到很好的确立，其执行受到许多障碍的阻碍。因此，我们建议实现以下目标：（1）探索一套新方法的可行性，以创建一个适当的随机化队列，其中包括体重指数为30-40 kg/m2的T2 DM患者，这些患者愿意随机分配到RYGB或强化医疗/生活方式干预组;（2）在试点随机试验中检查这种新的队列生成方案的效用，确定接近以实现适当样本量所需的数量，被动与主动数据收集机制的可靠性，同时进行的医疗保健利用测量的分配的准确性，以及最终的全面试验执行和保留所需的资源;（3）在这些随机化患者的子集中研究先天免疫改变的潜在作用（即，全身性和脂肪组织炎症）和适应性免疫（即，胰岛反应性T淋巴细胞）在RYGB抗糖尿病作用中的作用，并评估相关指标对未来临床试验的价值。

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. PUBLIC HEALTH RELEVANCE: The escalating pandemics of obesity and type 2 diabetes mellitus (T2DM) are among the most significant contributors to morbidity and mortality worldwide. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and dramatically ameliorates T2DM through mechanisms beyond just weight loss, but its role in diabetes management and the nature of its weight-independent anti-diabetes effects are not well established because of a paucity of appropriate randomized trials, the execution of which is hindered by numerous obstacles. We therefore propose to accomplish the following objectives: (1) explore the feasibility of a set of novel methods to create an appropriate randomization cohort of patients with T2DM and a body mass index of 30-40 kg/m2 who are willing to be randomized into either RYGB or an intensive medical/lifestyle intervention; (2) examine the utility of this novel cohort generation scheme in a pilot randomized trial, determining the number needed to approach to accomplish appropriate sample sizes, the reliability of passive vs. active data collection mechanisms, the accuracy of assignment of concurrent healthcare utilization measurements, and the resources required for eventual full-scale trial execution and retention; (3) study in a subset of these randomized patients the potential roles for alterations in innate immunity (i.e., systemic and adipose-tissue inflammation) and adaptive immunity (i.e., islet-reactive T lymphocytes) in the anti-diabetic effects of RYGB, and evaluate the value of related metrics for future clinical trials.