Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery

描述（由申请人提供）：Roux-en-Y胃旁路手术在84%的病例中导致2型糖尿病（T2DM）的完全、持久缓解，通常在手术后几天到几周内。越来越多的证据表明，这种戏剧性的现象不仅仅是与减肥和减少热量摄入有关的影响。RYGB介导体重无关的抗糖尿病作用的机制尚不清楚，阐明这些机制可能会导致新的糖尿病药物。“下肠假说”认为RYGB改善T2DM是通过创造一条肠道捷径，促进营养物质向远端肠的输送，刺激胰高血糖素样肽-1。然而，我们和其他人发现，在大鼠中，排除一小段近端小肠（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作用，而不依赖于食物摄入量、体重或远端肠道营养刺激的变化，从而导致另一种“上肠假说”。这两种假说都假设了可能涉及迷走神经的机制，迷走神经在RYGB效应中的作用尚不清楚。我们建议确定上肠假说是否在人类中有效，并阐明其机制，以及迷走神经在RYGB降血糖作用中的作用。在RYBG之前，患者将接受频繁的静脉滴注葡萄糖耐量试验（FS-IVGTT）和示指示剂增强的高胰岛素/正血糖钳夹（以测量胰岛素分泌和敏感性），在RYBG之后的最初几周进行3次，在此期间，近端小肠将被排除在营养接触之外，或暴露于通过留置胃管输送的营养物质中。相关的机制研究将在一种新的长期存活RYGB模型中进行，该模型是我们在过去3年中在胰岛素抵抗猪中开发的。奥沙巴猪将接受胃空肠造口术，以类似于RYBG的方式（但不影响胃）增强营养物质向远端肠的输送，在进行或不进行十二指肠排除以避免与摄入的营养物质接触。这两种手术都增加了远端肠道营养刺激，但都不会导致体重减轻；它们唯一的区别是是否存在适度的近端肠旁路。随着时间的推移，这些过程对葡萄糖稳态的影响将通过fs - ivgtt和最小模型来量化。对胰岛的长期影响将通过术前和术后2细胞增殖、新生、凋亡和质量的量化来评估。β细胞的功能和胰岛素分泌机制将在体外使用胰岛进行测定。将检查不同的胃肠道段，以确定产生相关肠肽的肠内分泌细胞的发育是否发生改变。为了检验迷走神经在RYGB效应中的作用，猪将在有或没有完全迷走神经切开术的情况下进行这项手术，并将进行上述所有的死前和死后测量。血浆GLP-1， GIP水平。PYY和ghrelin将在这两个物种的实验过程中在标准化的膳食中产生，以阐明这些肠道肽在我们观察到的变化中的作用。公共卫生相关性：了解Roux-en-Y胃旁路手术对体重无关的抗糖尿病影响的介导机制，并确定影响葡萄糖稳态的手术操作的可修改成分，可能会导致糖尿病护理中新的、更有效的治疗方法的发展。

DESCRIPTION (provided by applicant): 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 2-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. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms mediating the weight-independent anti-diabetes impact of Roux-en-Y gastric bypass surgery and identifying modifiable components of the surgical operation that impact glucose homeostasis may lead to the development of new, more effective treatments in diabetes care.