Metabolic and Endocrine Effects of Bariatric Surgery

减肥手术的代谢和内分泌影响

• 批准号: 10188510
• 负责人: Judith Korner
• 金额: $ 37.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188510
• 关键词: ART protein; Bariatrics; Beta Cell; Blood; Body Weight decreased; Brain; Caloric Restriction; Calories; Cell physiology; Cells; Chronic; Clinical Trials; Corticotropin; Diabetes Mellitus; Diet; Endocrine; FGF19 gene; Fasting; Functional disorder; Gastrectomy; Gastric Bypass; Goals; Hormonal; Hormones; Human; Hunger; Hydrocortisone; Hypothalamic structure; Impairment; Insulin; Insulin Resistance; Intervention; Intestines; Investigation; Life Style; Measurement; Measures; Medical; Metabolic; Morbid Obesity; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacotherapy; Plasma; Plasma Proteins; Prevalence; Procedures; Progress Reports; Proteins; Proteomics; Rodent; Sampling; Small Intestines; Testing; Therapeutic; Thinness; Time; adult obesity; bariatric surgery; blood glucose regulation; clinically significant; comorbidity; direct application; effective therapy; ghrelin; glycemic control; hypothalamic-pituitary-adrenal axis; improved; insulin sensitivity; intravenous glucose tolerance test; lifestyle intervention; novel; post intervention; prevent; protein B; protein activation; recidivism; response; therapeutic target; weight maintenance

Project Summary/Abstract Weight loss (WL) improves obesity-related co-morbidities such as type 2 diabetes mellitus (DM). Unfortunately, WL through life-style interventions has a high degree of recidivism and the paucity of safe, effective and affordable pharmacotherapy together with an increase in the prevalence of morbid obesity has led to a rise in bariatric procedures. Clinical trials in patients with DM show that improvements in glycemia vary between procedures and occur in the following order: Roux-en-Y gastric bypass (RYGB) > sleeve gastrectomy (SG) > laparoscopic adjustable gastric banding (LAGB) > medical/life-style therapy. This order mirrors the amount of WL with each intervention and is a major driver of glycemic improvement. We have shown profound changes unique to RYGB and SG in levels of hormones that make up the “gut-brain” and “enteroinsular” axes. The association of some of these hormones with insulin sensitivity (IS) and glycemia independent of WL strongly suggests that glycemic improvements after surgery occur in part through pathways that are distinct from just calorie restriction. A new direction of this application builds on our results showing that levels of fibroblast growth factor 19 (FGF19), a protein secreted by intestinal cells, are increased after RYGB and SG but not after low calorie diet (LCD). One of the effects of FGF19 is to improve IS, which in rodents occurs via suppression of agouti-related protein (AgRP) neurons in the hypothalamus. Another finding in rodents is that FGF19 ameliorates activation of the hypothalamic-pituitary-adrenal (HPA) axis, further adding to the growing evidence that operating on the gut changes brain activity. We have shown that measurement of plasma AgRP reflects central activity. Thus, in AIM ONE we will explore the “gut-brain-HPA” axis in humans and test the hypothesis that diet-induced WL causes an increase in plasma AgRP and activation of the HPA axis whereas equivalent WL after RYGB or SG do not produce such an increase. These findings are of clinical significance as preventing activation of the HPA axis may control hunger and allow for long-term maintenance of WL. In AIM TWO we will utilize proteomic analysis to further extend our investigations of WL dependent and independent mechanisms that may account for differences in metabolic outcomes between LCD, RYGB and SG. A number of experimental paradigms indicate that protein secreted from the proximal small intestine induces insulin resistance which provides a possible explanation as to why RYGB, which excludes this segment of the intestine, produces superior results compared with SG that are independent of WL. In the proposed Aims subjects will be carefully characterized with frequently sampled intravenous glucose tolerance tests and mixed meal tolerance tests. We expect results that will tease out mechanisms related to improvements in IS and beta-cell function that are independent of weight reduction and specific to RYGB or SG with the ultimate goal of optimizing surgical procedures and providing new non-surgical therapeutic targets for the treatment of DM and obesity.

项目概要/摘要 体重减轻 (WL) 可改善与肥胖相关的并发症，例如 2 型糖尿病 (DM)。 通过生活方式干预进行的 WL 累犯率很高，而且缺乏安全、有效和有效的方法 负担得起的药物治疗加上病态肥胖患病率的增加导致了 糖尿病患者的减肥治疗临床试验表明，血糖的改善效果因人而异。 手术并按以下顺序进行：Roux-en-Y 胃绕道手术 (RYGB) > 袖状胃切除术 (SG) > 腹腔镜可调节胃束带 (LAGB) > 医疗/生活方式治疗 该顺序反映了治疗量。 每次干预的 WL 是血糖改善的主要驱动力，我们已经显示出深刻的变化。 构成“肠脑”和“肠岛”轴的激素水平是 RYGB 和 SG 所独有的。 其中一些激素与胰岛素敏感性 (IS) 和血糖之间的关联与 WL 密切相关 表明手术后血糖的改善部分是通过不同于单纯手术的途径发生的。 该应用的新方向建立在我们显示成纤维细胞水平的结果之上。 生长因子 19 (FGF19) 是一种由肠细胞分泌的蛋白质，在 RYGB 和 SG 后增加，但在 RYGB 和 SG 后没有增加 低热量饮食 (LCD) FGF19 的作用之一是改善 IS，这在啮齿类动物中是通过抑制来实现的。 啮齿类动物下丘脑中刺鼠相关蛋白 (AgRP) 神经元的另一个发现是 FGF19。 改善下丘脑-垂体-肾上腺 (HPA) 轴的激活，进一步增加了越来越多的证据 我们已经证明，对肠道的操作会改变大脑活动。 因此，在 AIM ONE 中，我们将探索人类的“肠-脑-HPA”轴并检验这一假设。 饮食诱导的 WL 会导致血浆 AgRP 增加和 HPA 轴激活，而同等水平 RYGB 或 SG 后的 WL 不会产生这样的增加，这些发现具有临床意义。 阻止 HPA 轴的激活可以控制饥饿并允许长期维持 AIM 中的 WL。 两个我们将利用蛋白质组分析来进一步扩展我们对 WL 依赖性和独立性的研究 可能解释 LCD、RYGB 和 SG 之间代谢结果差异的机制。 实验范式表明近端小肠分泌的蛋白质诱导胰岛素 阻力提供了一个可能的解释，为什么 RYGB 排除了这一部分 与 SG 相比，与 WL 无关，可产生更好的结果。 将通过频繁采样的静脉内葡萄糖耐量试验和混合试验来仔细表征受试者的特征 我们预计膳食耐受性测试的结果将阐明与 IS 和改善相关的机制。 β 细胞功能与体重减轻无关，并且针对 RYGB 或 SG 具有最终目标 优化手术流程并为糖尿病的治疗提供新的非手术治疗靶点 和肥胖。

项目成果

FGF 19 and Bile Acids Increase Following Roux-en-Y Gastric Bypass but Not After Medical Management in Patients with Type 2 Diabetes.

2 型糖尿病患者在进行 Roux-en-Y 胃绕道手术后，FGF 19 和胆汁酸会增加，但在药物治疗后不会增加。

• 发表时间: 2016-05
• 影响因子: 2.9
• 作者: Sachdev, Saachi;Wang, Qi;Billington, Charles;Connett, John;Ahmed, Leaque;Inabnet, William;Chua, Streamson;Ikramuddin, Sayeed;Korner, Judith
• 通讯作者: Korner, Judith

The sum of many parts: potential mechanisms for improvement in glucose homeostasis after bariatric surgery.

许多部分的总和：减肥手术后改善葡萄糖稳态的潜在机制。

• 发表时间: 2014
• 影响因子: 4.2
• 作者: Nguyen, Kim T;Korner, Judith
• 通讯作者: Korner, Judith

Hypothalamic obesity in patients with craniopharyngioma: treatment approaches and the emerging role of gastric bypass surgery.

颅咽管瘤患者的下丘脑肥胖：治疗方法和胃绕道手术的新作用。

• 发表时间: 2012-03
• 影响因子: 3.8
• 作者: Page;Wardlaw, Sharon L;Khandji, Alexander G;Korner, Judith
• 通讯作者: Korner, Judith

Roux-en-Y Gastric Bypass Is Associated With Hyperinsulinemia But Not Increased Maximal β-Cell Function.

Roux-en-Y 胃绕道术与高胰岛素血症相关，但不增加最大β细胞功能。

• 发表时间: 2019-03-01
• 影响因子: 4.1
• 作者: Georgia, Annette;Asnis, Maria Cecilia Catilo;Febres, Gerardo;Tsang, Amanda;Bessler, Marc;Korner, Judith
• 通讯作者: Korner, Judith

Implantable gastric stimulator does not prevent the increase in plasma ghrelin levels that occurs with weight loss.

植入式胃刺激器不能阻止体重减轻时血浆生长素释放肽水平的增加。

• 发表时间: 2011-10
• 作者: Korner, Judith;Nandi, Anindita;Wright, Suzanne M;Waitman, Jonathan;McMahon, Donald J;Bessler, Marc;Aronne, Louis J
• 通讯作者: Aronne, Louis J