Determinants of Beta Cell Function Following Sleeve Gastrectomy in Adolescents

青少年袖状胃切除术后 β 细胞功能的决定因素

• 批准号: 9330152
• 负责人: Vibha Singhal
• 金额: $ 19.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330152
• 关键词: 1-Phosphatidylinositol 3-Kinase; 21 year old; Acute; Address; Adolescence; Adolescent; Adolescent obesity; Adult; Affect; Age; Award; Bariatrics; Beta Cell; Bile Acids; Biological Preservation; Body Weight Changes; Body Weight decreased; Caring; Cell physiology; Cells; Childhood; Clinical; Clinical Investigator; Collaborations; Comorbidity; Coupled; Data; Development; Development Plans; Diabetes Mellitus; Diabetes prevention; Diet; Distal; Early Intervention; Endocrinologist; Endocrinology; Evaluation; Fasting; Funding; Future; G-substrate; GPBAR1 gene; GTP-Binding Protein alpha Subunits, Gs; Gastrectomy; Gastroenterology; General Hospitals; Genetic; Genomics; Glycine; Glycogen; Goals; Grant; Health; Insulin; Insulin Resistance; Intervention; Intervention Trial; Intestinal Motility; Intestines; L Cells; Lead; Liquid substance; Massachusetts; Master' s Degree; Mediating; Mediator of activation protein; Medical; Medical Care Costs; Memory; Mentors; Metabolic; Metabolism; Morbid Obesity; Mus; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Operative Surgical Procedures; Oral; Outcome; Pancreas; Pathway interactions; Pediatrics; Pharmaceutical Preparations; Physiology; Population; Principal Investigator; Procedures; Process; Puberty; Public Health; Reporting; Research; Research Personnel; Safety; Solubility; Stress; Taurine; Training; Weight; Wild Type Mouse; Youth; age group; bariatric surgery; bone; burnout; career development; dehydroxylation; design; follow-up; functional improvement; gastrointestinal; glycemic control; gut microbiome; high risk; high risk population; improved; indexing; instructor; insulin secretion; medical schools; medical specialties; microbiome; microbiota; new therapeutic target; novel; obesity in children; obesity treatment; prevent; prospective; protective effect; receptor; success; therapeutic target

Project Summary Severe obesity in adolescence continues to rise and has far reaching metabolic consequences. Childhood obesity is responsible for $14 billion of direct medical care costs annually. It is thus essential to prevent obesity and its complications, which are crippling a third of the youth in the U.S. today. Bariatric surgery, particularly vertical sleeve gastrectomy (VSG), is being increasingly used to treat severe obesity. Evaluating metabolic changes after VSG and the mechanisms leading to these changes may help identify less invasive therapeutic targets for this condition. There is a significant improvement in glycemic control following surgery, primarily because of significant weight loss and associated improvement in insulin resistance and pancreatic function. Improving pancreatic function (or beta cell function) is especially important in adolescents because (i) their beta cells are under higher stress from the added insulin resistance of puberty, and (ii) the replicative potential of beta cells decreases with age and hence the maximal ability to preserve beta cells is during younger ages. There are no data regarding the outcomes of VSG in adolescents to date. Hence, in this proposal we will characterize the acute and long term changes in beta cell function and its determinants following VSG in adolescents, 14-21 years old. Moreover, a recent quest for mechanisms underlying these metabolic improvements post surgery has revealed that changes in bile acid secretion and composition and associated changes in the gut microbiome may be novel pathways associated with improving glycemic control. This proposal will prospectively follow 60 obese adolescents (30 undergoing usual medical care and 30 undergoing VSG) for 24 months and evaluate changes in bile acids and fecal microbiome after VSG. If the study identifies specific bile acid or fecal microbiome changes that are associated with improved beta cell function, this could form the basis for a future interventional trial. The proposed study will utilize several complementary sub- specialties- endocrinology, gastroenterology and genetics. The principal investigator, Dr. Singhal, is an Instructor in Pediatrics at Harvard Medical School and Pediatric Endocrinologist at Massachusetts General Hospital. Her long-term goal is to be an independent clinical investigator in the field of pediatric obesity and metabolism. Her career development will be closely guided by her co-mentors, Drs Misra, Bredella, Patti and Fasano, who together provide the required expertise in metabolic evaluation of obesity, bile acid physiology and microbiome analysis. Execution of the proposed project will provide Dr. Singhal with hands-on training in metabolic and genomic assessments in obese adolescents and pave way for future collaborations. In addition, the career development plan incorporates completion of a Master's degree in Public Health. This mentored research award will provide Dr. Singhal with the additional training critical to her success as an independent investigator in pediatric obesity. Understanding the mechanisms of beta cell function improvement will lead to the design of subsequent interventional trials to optimize metabolic health in adolescents with obesity.

项目概要 青春期严重肥胖率持续上升，并对代谢产生深远影响。童年 肥胖每年造成 140 亿美元的直接医疗费用。因此预防肥胖至关重要 及其并发症，正在使当今美国三分之一的年轻人陷入瘫痪。减肥手术，特别是 垂直袖状胃切除术（VSG）越来越多地用于治疗严重肥胖。评估代谢 VSG 后的变化以及导致这些变化的机制可能有助于确定侵入性较小的治疗方法 针对这种情况的目标。手术后血糖控制有显着改善，主要是 因为体重显着减轻以及胰岛素抵抗和胰腺功能的相关改善。 改善胰腺功能（或 β 细胞功能）对于青少年尤其重要，因为 (i) β 细胞因青春期胰岛素抵抗增加而承受更高的压力，以及 (ii) 复制潜力 β细胞的数量随着年龄的增长而减少，因此保存β细胞的最大能力是在年轻的时候。 迄今为止，尚无关于青少年 VSG 结果的数据。因此，在本提案中，我们将 描述 VSG 后 β 细胞功能的急性和长期变化及其决定因素 青少年，14-21岁。此外，最近对这些代谢背后机制的探索 术后的改善表明胆汁酸分泌和成分的变化以及相关 肠道微生物组的变化可能是与改善血糖控制相关的新途径。这 该提案将前瞻性地跟踪 60 名肥胖青少年（其中 30 名正在接受常规医疗护理，30 名正在接受 VSG）24个月，并评估VSG后胆汁酸和粪便微生物组的变化。如果研究确定 与改善 β 细胞功能相关的特定胆汁酸或粪便微生物组变化，这可能 为未来的干预试验奠定基础。拟议的研究将利用几个互补的子项目 专业-内分泌学、胃肠病学和遗传学。首席研究员 Singhal 博士是一名 哈佛医学院儿科讲师和马萨诸塞州综合医院儿科内分泌学家 医院。她的长期目标是成为儿童肥胖领域的独立临床研究者 代谢。她的职业发展将受到她的共同导师 Misra 博士、Bredella 博士、Patti 博士和 Fasano，他们共同提供肥胖代谢评估、胆汁酸生理学方面所需的专业知识 和微生物组分析。拟议项目的执行将为 Singhal 博士提供以下方面的实践培训： 肥胖青少年的代谢和基因组评估，并为未来的合作铺平道路。此外， 职业发展计划包括完成公共卫生硕士学位。此次辅导的 研究奖将为 Singhal 博士提供额外的培训，这对她作为独立专家的成功至关重要 小儿肥胖症研究者。了解 β 细胞功能改善的机制将导致 设计后续干预试验以优化肥胖青少年的代谢健康。