Physiologic response to bariatric surgery and the impact of adjunct semaglutide - in adolescents (the PRESSURE trial)

项目摘要/摘要 代谢和减肥手术(MBS)治疗儿童重度肥胖症越来越常见。年轻时的MBS 年龄意味着几十年后才能保持或增强其心脏代谢和其他健康益处。虽然卑鄙 在MBS后体重下降是显著的，美国队列中50%的青少年持续严重 肥胖症&3年后。我们还发现，25%的年轻人体重在6个月内显著增加 术后5年。此外，年轻人和成年人对MBS的共病反应似乎不同。 在年轻人中，很少有人知道MBS后体重下降的预测因素，也没有足够的机械性数据来评估 生理因素作为潜在的预测因素。此外，缺乏深入的心脏代谢表型， 这可能有助于定义MBS后的残余风险，而不仅仅是体重减轻。我们假设1)生理上的 肠多肽、身体成分和静息代谢率(RMR)的表型可以部分解释变异性。 在青少年MBS减肥中(目标1)，胰岛素敏感性(IS)的改善将与有利的 心血管改变与体重指数改变无关(AIM 2)，以及2)术后辅助性高血糖素样改变 多肽-1(GLP-1)药物治疗将增加青少年MBS的益处，但手术反应不佳。我 提出一项两阶段设计：一项为期一年的前瞻性研究，测量肠肽、身体成分、 RMR和心脏代谢测量(IS、24小时血压、结构/功能超声心动图、动脉 僵硬，心脏自主神经功能)从MBS前到MBS后1年(n=30)，2)随机、双盲、6- 在体重指数下降20%的12-24岁青少年(n=18)中，停药后1-2年，赛马路德与安慰剂进行月度干预。 作为营养学系儿科助理教授，拥有扎实的出版物和资助金 资金记录和新兴的临床试验经验，我在个性化领域确立了自己的地位 儿童肥胖医学。我展望了未来青少年体重管理的诊断工具和干预措施。 这是根据个人潜在的(病态)生理、价值观和社会环境影响量身定做的。一个 K23将支持以下研究目标：1)确定MBS机制的生理表型 和心脏代谢反应，使用以前在年轻人中没有报道的强健措施，2)完成第一个 GLP-1受体激动剂在青年MBS后的随机对照试验，以及3)从不同的 这一群体特别填补了未被充分代表的西班牙裔青年的空白。我的职业发展计划是认真的 旨在1)学习如何纵向执行和解释肠肽、身体的核心动态测量 成分、能量平衡、胰岛素敏感性和心血管健康。这些措施的经验将 产生一个通用的工具箱，这将是高度可翻译的未来临床干预试验的儿童肥胖。2) 获得较长学习方案的招聘/保留经验(18个月)，以及3)了解传统 研究设计可以为随后的R01提供更灵活的适应性临床试验干预措施。

PROJECT SUMMARY/ABSTRACT Metabolic and bariatric surgery (MBS) to treat pediatric severe obesity is increasingly common. MBS at younger ages means decades longer to preserve or enhance its cardiometabolic and other health benefits. While mean weight loss after MBS is substantial, >50% of adolescents in prospective US cohorts have persistent severe obesity >3 years later. We have also found that 25% of youth show significant weight regain 6 months through 5 years postoperatively. Additionally, comorbidity response to MBS appears to differ between youth and adults. In youth, few predictors of weight loss after MBS are known and there is insufficient mechanistic data evaluating physiologic factors as potential predictors. Further, there is an absence of in-depth cardiometabolic phenotyping, which could help to define residual risk post MBS beyond weight loss alone. We hypothesize that 1) physiologic phenotypes in gut peptides, body composition, and resting metabolic rate (RMR) will partially explain variability in MBS weight loss in adolescents (Aim 1), that improved insulin sensitivity (IS) will be associated with favorable cardiovascular changes independent of BMI change (Aim 2), and 2) Adjunctive postoperative glucagon-like peptide-1 (GLP-1) pharmacotherapy will augment MBS benefits in youth with suboptimal surgical response. I propose a 2-phase design: a 1-year prospective study measuring changes in gut peptides, body composition, RMR, and cardiometabolic measures (IS, 24 hour blood pressure, echocardiogram for structure/function, arterial stiffness, cardiac autonomic function) from pre- to 1 year post-MBS (n=30), 2) A randomized, double-blinded, 6- month intervention of semaglutide vs placebo 1-2 years postop in 12-24 year olds with <20% BMI loss (n=18). As an Assistant Professor in the Department of Pediatrics Section of Nutrition with a solid publication and grant funding record, and emerging clinical trial experience, I am establishing myself within the field of personalized pediatric obesity medicine. I envision future diagnostic tools and interventions for weight management in youth that are tailored to an individual’s underlying (patho)physiology, values, and socioenvironmental influences. A K23 would support the following research goals: 1) define physiologic phenotypes underlying MBS mechanism and cardiometabolic response using robust measures not previously reported in youth, 2) complete the first randomized controlled trial of a GLP-1 receptor agonist in youth post-MBS, and 3) contribute data from a diverse cohort that particularly fills gaps in under-represented Hispanic youth. My career development plan is carefully constructed to 1) learn how to longitudinally perform and interpret core dynamic measures of gut peptides, body composition, energy balance, insulin sensitivity, and cardiovascular health. Experience with these measures will yield a versatile toolbox that will be highly translatable to future clinical intervention trials in pediatric obesity. 2) gain experience with recruitment/retention for a longer study protocol (18 months), and 3) learn how traditional study designs can inform more nimble adaptive clinical trial interventions for a subsequent R01.