Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery

胃肠手术后血糖改善的机制

• 批准号: 8288919
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 48.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288919
• 关键词: Address; Affect; Anatomy; Animals; Apoptosis; Area; Attenuated; Bariatrics; Beta Cell; Body Weight; Body Weight decreased; Bypass; Cannulas; Caring; Cell Proliferation; Cell physiology; Cells; Cessation of life; Clinical; Collaborations; Consumption; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Disease remission; Distal; Duodenum; Eating; Energy Intake; Enteroendocrine Cell; Euglycemic Clamping; Evaluation; Exclusion; Exposure to; Family suidae; Food; Gastric Bypass; Gastric Stump; Gastrointestinal Surgical Procedures; Gastrointestinal tract structure; Gastrostomy; Glucose Clamp; Glucose tolerance test; Goals; Growth; Human; Hyperplasia; In Vitro; Insulin; Insulin Resistance; Intervention; Intestinal Bypasses; Intestines; Islet Cell; L Cells; Lead; Long-Term Effects; Measurement; Measures; Mediating; Mediator of activation protein; Medicine; Methods; Modeling; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Ostomy; Outcome; Pancreas; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Population; Postoperative Period; Primitive foregut structure; Procedures; Process; Rattus; Research Design; Resolution; Rodent; Role; Sampling; Small Intestines; Stomach; Study models; Testing; Time; Tracer; Tube; Upper digestive tract structure; Vagotomy; Vagus nerve structure; Variant; Visceral; Weight; abstracting; bariatric surgery; blood glucose regulation; cytochrome c; design; detection of nutrient; diabetic; diabetic patient; effective therapy; experience; gastric inhibitory polypeptide receptor; gastrointestinal; gastrojejunostomy; ghrelin; glucagon-like peptide; glucose metabolism; glycemic control; improved; in vivo; incretin hormone; insulin secretion; insulin sensitivity; intervention effect; intravenous glucose tolerance test; islet; jejunum; mRNA Expression; mitochondrial membrane; novel; operation; protein expression; release of sequestered calcium ion into cytoplasm; research study; theories

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.

项目摘要 Roux-en-Y胃旁路手术可使84%的2型糖尿病（T2 DM）患者完全、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， 这一现象的结果超出了与体重减轻和减少热量摄入有关的影响。的 介导RYGB的体重非依赖性抗糖尿病作用的机制尚不清楚， 他们可能会导致新的糖尿病药物。“下肠道假说”假设RYGB改善了 T2 DM通过建立肠道捷径来增强营养输送到远端肠道，刺激胰高血糖素- 比如肽-1。然而，我们和其他人发现，在大鼠中，排除近端小的短段， 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， 不依赖于食物摄入、体重或远端肠道营养刺激的变化，导致 替代“上肠假说”。这两种假说都证实了可能涉及迷走神经的机制 神经，其中的作用RYGB的影响是未知的。我们建议确定上层是否 肠道假说在人类中是有效的，并阐明其机制，以及迷走神经在RYGB中的作用 血糖效应人类将经历频繁采样的静脉内葡萄糖耐量试验（FS-IVGTT）和示踪剂- RYBG前增强高胰岛素/正常血糖钳夹（测量胰岛素分泌和敏感性）， 在之后的前几周内进行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年开发的新型长期生存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， 远端肠道以类似于RYBG的方式（但不影响胃），使用或 而不排除十二指肠与摄入的营养物质接触。两种手术均增加远端肠营养 刺激，两者都不会导致体重减轻;它们唯一的区别是存在或不存在适度的 近端肠旁路术这些程序对葡萄糖稳态的影响将随着时间的推移进行量化 FS-IVGTT和最小建模。对小岛的长期影响将通过以下方式进行评估： 细胞增殖、新生、凋亡和质量的操作定量。β细胞功能和 胰岛素分泌的机制将使用灌注的胰岛在体外确定。各种胃肠道节段 将进行检查，以确定是否改变肠内分泌细胞的发展， 产生相关的肠肽。为了检查迷走神经在RYGB效应中的作用，猪将经历 这项手术有或没有完全迷走神经切断术，以及所有上述的死亡前和死亡后的测量， 将被制造。GLP-1、GIP的血浆水平。PYY和生长激素释放肽将在标准化膳食中产生 在这两个物种的这些实验中，以澄清这些肠道肽在我们观察到的变化中的作用。