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: 7991756
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 60.14万
• 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/7991756
• 关键词: Address; Adherence; Adipose tissue; Adult; Adverse event; Area; Arts; Asses; Autoimmunity; Back Pain; 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; Guidelines; Health; Health Maintenance Organizations; Health system; Healthcare; Healthcare Systems; Hour; Human; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Insulin Resistance; 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-based; 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胃旁路（RYGB）通过不仅减轻体重减轻的机制，可以极大地改善2型糖尿病（T2DM）。但是，由于缺乏随机临床试验（RCT），与非手术糖尿病护理相比，RYGB的风险效益比尚不清楚，尤其是对于肥胖较少的患者而言。适当的RCT的障碍包括招募足够数量的知情患者的挑战，这些患者愿意被随机分配到手术或非手术方法，他们具有干预措施的资金来源，并且不被强迫介入干预部门，以及在纵向数据收集和DELINEATE机构的纵向数据收集和纵向数据收集中的操作问题。我们建议通过追求3个目标来解决这些障碍。首先，我们将确定一种新型方法的可行性，以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RYGB，并愿意在BMI 30-35 kg/m2的患者中这样做。我们将利用该网络的数据库识别具有T2DM的成年人，而BMI为30-40 kg/m2。将对这些患者（4,000-6,000名）的足够数量进行调查，以确定那些在医疗与糖尿病和肥胖症的手术治疗方面没有强烈偏爱的人。该子集将暴露于我们开发和验证的新型，标准化的共享制作（SDM）工具（SDM）工具（该领域中唯一的此类工具），该工具有助于患者探索两种治疗方案的风险和好处，然后将评估他们的“随机化意愿”。其次，在SDM过程之后，将随机将一群保持在等式的患者，以接受RYGB或最先进的饮食，运动和药物治疗的糖尿病/肥胖药物治疗的最先进的医疗/生活方式干预，我们帮助我们在先前的RCT中开发和测试。可行性RCT的目的是证明我们新颖的队列生成计划的实用性，以确定完成适当样本量所需的数量，以评估被动和主动数据收集机制的可靠性，以确定一致的医疗保健利用（HCU）测量值（HCU）测量的准确性，并确定对最终进行完整的实施和重新定期进行的资源。第三，我们将评估包括一组新型指标来阐明RYGB的抗糖尿病机制的有用性。在随机患者中，我们将测试RYGB改变先天和/或适应性免疫以改善葡萄糖稳态的假设。 由巨噬细胞和脂肪组织和胰岛中T淋巴细胞驱动的慢性炎症在T2DM发病机理中起关键作用，我们假设RYGB逆转了这些过程与IT促进的体重损失不成比例。我们将通过量化脂肪组织活检，全身性炎症和抗ISLET T细胞反应性的细胞炎症来检验这一假设，在基线时，干预后2周和7％的体重减轻，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（T2DM）的升级是全球发病率和死亡率的最重要的贡献者之一。 roux-en-y胃旁路（RYGB）手术可通过不仅减肥的机制来大大减轻T2DM，但是由于适当的随机试验的依赖性，由于糖尿病管理的作用及其在糖尿病管理中的作用并不能很好地确定其无关紧要的抗糖尿病效应，因此无法很好地确定。因此，我们建议实现以下目标：（1）探索一组新方法的可行性，以创建适当的T2DM患者和30-40 kg/m2患者的随机分组，这些患者愿意被随机分为RYGB或强化的医疗/生活方式干预； （2）在试点随机试验中检查了这种新型队列生成方案的实用性，确定了实现适当样本量所需的数量，被动数据收集机制的可靠性，同时进行医疗保健利用测量所需的分配的准确性以及最终的全面试用试验和退休所需的资源； （3）在这些随机患者的子集中进行研究，其先天免疫力改变（即系统性和脂肪 - 组织炎症）的潜在作用和适应性免疫（即胰岛反应性T淋巴细胞）在Rygb的抗降亚效应中的RYGB效应中的RYGB效应中的潜在作用（即胰岛反应性T淋巴细胞）的作用。