Metabolic and Endocrine Effects of Bariatric Surgery

项目概要/摘要 体重减轻（WL）可改善肥胖相关的合并症，如2型糖尿病（DM）。不幸的是， 通过生活方式干预的WL具有较高的累犯率，缺乏安全、有效和 负担得起的药物治疗加上病态肥胖症患病率的增加导致了 减肥手术糖尿病患者的临床试验表明， 手术并按以下顺序进行：Roux-en-Y胃旁路术（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。这个订单反映了 WL与每次干预相关，并且是血糖改善的主要驱动力。我们已经显示出深刻的变化 RYGB和SG在组成"肠-脑"和"肠-岛"轴的激素水平方面是独特的。的 这些激素中的一些与胰岛素敏感性（IS）和胰岛素抵抗密切相关， 表明，手术后血糖的改善部分是通过不同于仅仅是 卡路里限制。这项应用的新方向建立在我们的结果表明，成纤维细胞的水平， 生长因子19（FGF19），一种由肠细胞分泌的蛋白质，在RYGB和SG后增加，但在 低热量饮食（LCD）。FGF 19的作用之一是改善IS，其在啮齿动物中通过抑制 下丘脑AgRP神经元的变化。在啮齿类动物中的另一项发现是， 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 肠道手术会改变大脑活动我们已经表明，等离子体AgRP的测量反映了 中心活动。因此，在AIM ONE中，我们将探索人类的“肠-脑-HPA”轴并验证假设 饮食诱导的WL导致血浆AgRP增加和HPA轴激活，而相当于 在RYGB或SG之后的WL不产生这样的增加。这些发现具有临床意义， 防止HPA轴的激活可以控制饥饿并允许WL的长期维持。在aim中 第二，我们将利用蛋白质组学分析进一步扩展我们对WL依赖性和非依赖性的研究。 可能解释LCD、RYGB和SG之间代谢结果差异的机制。一些 的实验范例表明，从近端小肠分泌的蛋白质诱导胰岛素 电阻，这提供了一个可能的解释，为什么RYGB，其中排除了这一部分的 肠，产生上级的结果相比，SG是独立的WL。在拟议的目标中， 受试者将通过频繁采样的静脉内葡萄糖耐量试验仔细表征， 膳食耐受性试验我们期待的结果将梳理出机制有关的改进是， β-细胞功能，其独立于体重减轻，并特异于RYGB或SG，最终目标是 为糖尿病的治疗提供新的非手术治疗靶点 和肥胖。

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.