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

手术与药物治疗糖尿病的可行性、有效性和机制

• 批准号: 8130737
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 57.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-18 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130737
• 关键词: Address; Adherence; Adipose tissue; Adult; Adverse event; Area; Asses; Autoimmunity; Back; Bariatrics; Behavior Therapy; Behavioral; Benefits and Risks; Biological Markers; Biopsy; Blood specimen; Body Weight; Body Weight decreased; Body mass index; Calculi; Caring; Cells; Chronic; Clinic; Clinical; Clinical Trials; Collaborations; Computerized Medical Record; Coupled; Data; Data Collection; Databases; Decision Aid; Decision Making; Development; Diabetes Mellitus; Disease; Disease remission; Eating; Educational Activities; Electronics; Eligibility Determination; Enrollment; Equilibrium; Equipoise; Evaluation; Exercise; Exposure to; Failure; Feasibility Studies; Flow Cytometry; Fostering; Foundations; Fred Hutchinson Cancer Research Center; Funding Agency; Future; Gastric Bypass; Generations; Genetic Crossing Over; Glycosylated hemoglobin A; Goals; Gold; Health; Health Maintenance Organizations; Health system; Healthcare; Healthcare Systems; Hour; Human; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Insulin; Insurance; Insurance Coverage; Interdisciplinary Study; Internet; Intervention; Knowledge; Letters; Life Style; Link; Longitudinal Studies; Measurement; Measures; Medical; Medical Records; Medical center; Medicine; Methodology; Methods; Metric; Minority; Morbid Obesity; Morbidity - disease rate; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Operative Surgical Procedures; Outcome; Outcome Measure; Pathogenesis; Patients; Performance; Pharmacotherapy; Physical Fitness; Physical activity; Physicians; Play; Process; Productivity; Proxy; Qualifying; Quality of life; Questionnaires; Random Allocation; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recruitment Activity; Relative (related person); Reporting; Research; Research Design; Research Institute; Research Personnel; Research Project Grants; Resources; Role; Safety; Sample Size; Scheme; Scientist; Surveys; System; T-Lymphocyte; Testing; Time; Uninsured Medical Expense; United States National Institutes of Health; Universities; Update; Washington; Weight; Work; adaptive immunity; arm; autoreactive T cell; autoreactivity; bariatric surgery; base; blood glucose regulation; case-by-case basis; cell type; clinical care; cohort; cost; design; diabetes management; diabetic; diet and exercise; experience; fasting plasma glucose; health care delivery; health care service utilization; immunoregulation; improved; in vitro Assay; instrument; interest; islet; lifestyle intervention; macrophage; meetings; member; moderate obesity; mortality; neutrophil; novel; novel strategies; obesity management; obesity treatment; operation; pandemic disease; patient oriented; preference; programs; prospective; public health relevance; randomized trial; risk benefit ratio; shared decision making; therapy design; tool; treatment as usual; trial comparing; willingness

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.

描述(由申请人提供)：Roux-en-Y胃搭桥术(RYGB)显著改善2型糖尿病(T2 DM)，其机制除了减肥外，还知之甚少。然而，由于缺乏随机临床试验(RCT)，RYGB与非手术糖尿病治疗相比的风险-收益比尚不清楚，特别是对于肥胖程度较轻的患者。合适的随机对照试验的障碍包括在招募足够数量的知情患者方面面临挑战，这些患者愿意被随机分配到手术或非手术方法中，这些患者有资金来源进行任何一种干预，并且没有被迫进入干预组，以及纵向数据收集和描述T2 DM改善机制的指标的可用性方面的操作问题。我们建议通过追求3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，从一个涵盖BMI和GT；35 kg/m2患者的RYGB的综合医疗系统的成员中产生一个随机队列，并愿意在本研究中对那些BMI为30-35 kg/m2的患者这样做。我们将利用这个网络的数据库来识别患有T2 DM和BMI为30-40 kg/m2的成年人。将对足够数量的这些患者(4,000-6,000人)进行调查，以确定那些在糖尿病和肥胖症的内科和外科治疗方面没有强烈偏好的患者。这一子集将接触到我们开发和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好处，之后将评估他们的“随机化意愿”。其次，在SDM过程后保持平衡的一组患者将被随机分配到RYGB或接受我们帮助开发并在先前的RCT中测试的针对糖尿病/肥胖症的饮食、锻炼和药物疗法的最先进的强化医疗/生活方式干预。这一可行性随机对照试验的目标将是展示我们新的队列生成方案的效用，确定完成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，确定分配并发医疗利用(HCU)测量的准确性，以及确定最终全面试验执行和保留所需的资源。第三，在未来的试验中，我们将评估包括一组新的指标来阐明RYGB的抗糖尿病机制的有用性。在随机分组的患者中，我们将检验RYGB改变先天和/或获得性免疫以改善血糖稳态的假设。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的发病机制中起着关键作用，我们假设RYGB逆转这些过程的比例与其促进的体重减轻不成比例。我们将通过量化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，这些随机分组在基线、干预后2周和体重减轻7%时进行量化，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，是全世界发病率和死亡率的最大贡献因素之一。Roux-en-Y胃旁路(RYGB)手术可显著减轻体重，并通过除减肥之外的其他机制显著改善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非重量依赖的抗糖尿病效果的性质尚未得到很好的确定，而且该试验的实施受到许多障碍的阻碍。因此，我们建议完成以下目标：(1)探索一套新方法的可行性，以创建一个适当的随机队列的T2 DM患者和30-40公斤/平方米的体重指数愿意被随机分为RYGB或强化医疗/生活方式干预的患者；(2)在试点随机试验中检查这种新的队列生成方案的效用，确定实现适当样本量所需的数量，被动和主动数据收集机制的可靠性，同步医疗利用测量的分配的准确性，以及最终全面试验执行和保留所需的资源；(3)在这些随机患者中研究先天免疫(即全身和脂肪组织炎症)和获得性免疫(即胰岛反应性T淋巴细胞)的变化在RYGB抗糖尿病效果中的潜在作用，并评估相关指标在未来临床试验中的价值。