Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery

项目摘要 Roux-en-Y胃旁路手术导致84%的2型糖尿病(T2 DM)完全、持久缓解 病例，通常在手术后几天到几周内。越来越多的证据表明，这种戏剧性的 这一现象是除了与减肥和减少卡路里摄入量有关的影响外的其他因素造成的。这个 RYGB的非体重依赖性抗糖尿病作用的机制尚不清楚，目前正在阐明 它们可能会带来新的糖尿病药物。“下肠道假说”假设RYGB改善 通过创造一条肠道捷径来加强营养向远端肠道的输送，刺激胰高血糖素- 就像多肽-1。然而，我们和其他人发现，在老鼠身上，排除近端小段的一小段 肠道(主要是十二指肠)与摄入的营养物质接触会产生直接的抗糖尿病效果， 与食物摄入量、体重或远端肠道营养刺激的变化无关，导致 另一种“上肠道假说”。这两种假说都假定可能涉及迷走神经的机制。 神经，其在RYGB效应中的作用尚不清楚。我们建议确定上级是否 肠道假说在人类中是有效的，并阐明了其机制以及迷走神经在RYGB中的作用 升糖作用。人类将接受频繁采样的静脉葡萄糖耐量试验(FS-IVGTT)和示踪剂- 增强的高胰岛素/正血糖钳夹(用于测量胰岛素分泌和敏感性) 3次，在此期间，近端小肠将被排除在 营养素接触或暴露于通过留置胃管输送的营养素。相关机构学 研究将在我们在过去3年中开发的一种新的长期生存RYGB模型中进行 在胰岛素抵抗的猪身上。Ossabaw猪将接受胃空肠吻合术，这将增强营养输送到 以类似于RYBG的方式(但不影响胃)的远端肠道，使用或 不排除十二指肠与摄入的营养物质接触。这两种手术都增加了远端肠道的营养 刺激，都不会导致减肥；他们唯一的区别是有没有适度的 近端肠道搭桥术。这些过程对血糖稳态的影响将随着时间的推移而量化。 使用FS-IVGTT和最小建模。对岛屿的长期影响将在实施前和之后进行评估 对细胞增殖、新生、凋亡和质量进行操作量化。β细胞功能和 胰岛素分泌的机制将在体外使用灌流的胰岛来确定。各种胃肠道段 将被检查以确定在肠内分泌细胞的发育中是否发生了变化 相关的肠肽也会产生。为了研究迷走神经在RYGB效应中的作用，猪将进行 无论是否完全切断迷走神经，以及上述所有的死前和死后测量 都会被制造出来。血浆GLP-1、GIP水平。PYY和Ghrelin将在标准化膳食中生产 通过在这两个物种中的这些实验，来澄清这些肠肽在我们观察到的变化中的作用。

Project Abstract Roux-en-Y gastric bypass surgery causes complete, durable remission of type 2 diabetes (T2DM) in 84% of cases, typically within a few days to weeks after surgery. Mounting evidence indicates that this dramatic phenomenon results from effects beyond those related to weight loss and reduced caloric intake alone. The mechanisms mediating the weight-independent anti-diabetes impact of RYGB are unknown, and elucidating them could lead to new diabetes medicines. The "lower intestinal hypothesis" postulates that RYGB improves T2DM by creating an intestinal shortcut to enhance nutrient delivery to the distal bowel, stimulating glucagon- like peptide-1. However, we and others have found that in rats, exclusion of a short segment of proximal small bowel (primarily the duodenum) from contact with ingested nutrients exerts direct anti-diabetic effects, independent of changes in food intake, body weight, or distal intestinal nutrient stimulation, leading to an alternate "upper intestinal hypothesis". Both hypotheses posit putative mechanisms that may involve the vagus nerve, the role of which in the effects of RYGB is unknown. We propose to determine whether the upper intestinal hypothesis is valid in humans and to clarify its mechanisms, as well as the role of the vagus in RYGB glycemic effects. Humans will undergo frequently sampled I.V. glucose tolerance tests (FS-IVGTT) and tracer- enhanced hyperinsulinemic/euglycemic clamps (to measure insulin secretion and sensitivity) before RYBG and 3 times in the first few weeks afterward, during which the proximal small bowel will either be excluded from nutrient contact or exposed to nutrients delivered through an indwelling gastric cannula. Related mechanistic studies will be performed in a novel long-term-survival RYGB model we have developed over the past 3 years in insulin-resistant pigs. Ossabaw pigs will undergo a gastrojejunostomy, which enhances nutrient delivery to the distal bowel in a manner similar to RYBG (but without affecting the stomach), performed either with or without duodenal exclusion from contact with ingested nutrients. Both operations increase distal bowel nutrient stimulation and neither causes weight loss; their only difference is the presence or absence of a modest proximal intestinal bypass. Effects of these procedures on glucose homeostasis will be quantified over time with FS-IVGTTs and minimal modeling. Long-term impacts on islets will be assessed with pre- and post- operative quantifications of ¿-cell proliferation, neogenesis, apoptosis, and mass. Beta-cell function and mechanisms of insulin secretion will be determined in vitro using perifused islets. Various GI tract segments will be examined to ascertain whether alterations in the development of enteroendocrine cells producing relevant gut peptides occur. To examine the role of the vagus nerve in the effects of RYGB, pigs will undergo this operation with or without a complete vagotomy, and all of the above pre- and post-mortem measurements will be made. Plasma levels of GLP-1, GIP. PYY, and ghrelin will be made during standardized meals throughout these experiments in both species, to clarify roles for these gut peptides in changes we observe.