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（T2 DM）完全、持久缓解，通常在术后几天至几周内。越来越多的证据表明，这一戏剧性的现象是由体重减轻和热量摄入减少以外的影响造成的。介导RYGB的体重非依赖性抗糖尿病作用的机制尚不清楚，阐明它们可能导致新的糖尿病药物。“下肠假说”假定RYGB通过产生肠捷径以增强营养物递送至远端肠、刺激胰高血糖素样肽-1来改善T2 DM。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，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，导致替代的“上肠假说”。这两种假设都是假定的机制，可能涉及迷走神经，其在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血糖效应中的作用。在RYBG之前和之后的前几周内，人类将接受频繁采样的静脉内葡萄糖耐量试验（FS-IVGTT）和示踪剂增强的高胰岛素血症/正常血糖钳夹（以测量胰岛素分泌和敏感性）3次，在此期间，近端小肠将被排除营养接触或暴露于通过留置胃插管输送的营养。相关机制研究将在我们过去3年在胰岛素抵抗猪中开发的新型长期存活RYGB模型中进行。Ossabaw猪将接受胃空肠吻合术，以类似于RYBG的方式（但不影响胃）增强营养物质向远端肠道的输送，在有或没有十二指肠与摄入的营养物质接触的情况下进行。这两种手术都增加了远端肠道营养刺激，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道旁路。将使用FS-IVGTT和最小建模定量这些程序对葡萄糖稳态随时间的影响。将通过术前和术后2-细胞增殖、新生、凋亡和质量的定量来评估对胰岛的长期影响。将使用灌注的胰岛在体外确定β细胞功能和胰岛素分泌机制。将检查各种胃肠道节段，以确定是否发生产生相关肠肽的肠内分泌细胞发育的变化。为了检查迷走神经在RYGB效应中的作用，猪将在有或没有完全迷走神经切断术的情况下进行该手术，并且将进行所有上述宰前和宰后测量。GLP-1、GIP的血浆水平。PYY和ghrelin将在两个物种的这些实验中在标准化膳食期间制备，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：了解调节Roux-en-Y胃旁路手术的体重非依赖性抗糖尿病影响的机制，并确定影响葡萄糖稳态的手术操作的可修改组件，可能会导致开发新的，更有效的糖尿病治疗方法。

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.