Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery

胃肠手术后血糖改善的机制

• 批准号: 8094301
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 49.7万
• 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/8094301
• 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; Health; 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; 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

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.

描述（由申请人提供）：Roux-en-Y胃旁路手术会导致2型糖尿病（T2DM）的持久缓解，其中84％的病例通常在手术后几天至几周内。越来越多的证据表明，这种戏剧性现象是由与体重减轻和仅减少热量摄入相关的作用产生的。 RYGB介导的无关抗糖尿病的影响的机制尚不清楚，阐明它们可能导致新的糖尿病药物。 “下肠假说”假设RYGB通过创建肠道快捷方式来改善T2DM，从而增强营养素到远端肠的递送，从而刺激胰高血糖素像肽-1。但是，我们和其他人发现，在大鼠中，排除了与摄入的养分的接触直接的抗糖尿病效应，而排除了一小段近端小肠（主要是十二指肠），而与食物摄入量，体重或远端肠道营养刺激的变化无关，导致了交替的“上层肠道假设”。这两个假设都假定的推定机制可能涉及迷走神经，而RYGB的作用在RYGB的作用中的作用尚不清楚。我们建议确定上肠道假设在人类中是否有效，并阐明其机制以及迷走神经在RYGB血糖作用中的作用。人类会经常进行静脉注射。葡萄糖耐受性测试（FS-IVGTT）和示踪剂增强的高胰岛素/优质血糖夹（以测量rybg之前的胰岛素分泌和敏感性），在最初的几周内进行了3次，在此之后，在此期间，近调小肠将通过营养式或易于营养不良。相关的机械研究将在我们在过去3年中在胰岛素耐药的猪中开发的新型长期生存RYGB模型中进行。 Ossabaw Pigs将进行胃肠道造口术，从而以类似于RYBG（但不会影响胃）的方式增强营养素到远端肠道的递送，并以或没有十二指肠排除在与摄入的营养素接触的情况下进行。这两种操作都会增加肠营养素的远端刺激，并且都不会导致体重减轻。他们唯一的区别是存在或不存在适度的近端肠旁门。这些程序对葡萄糖稳态的影响将随着时间的流逝而通过FS-IVGTT和最小的建模进行量化。对胰岛的长期影响将通过2细胞增殖，新生成，凋亡和质量的手术前和手术后进行评估。 β细胞功能和胰岛素分泌的机制将在体外使用perifused Islet在体外确定。将检查各种胃肠道段，以确定是否发生了产生相关肠肽的肠内内分泌细胞发展的改变。为了检查迷走神经在RYGB作用中的作用，猪会在有或没有完全迷走道的情况下进行此操作，并且将进行上述所有验尸测量。 GLP-1的血浆水平，GIP。在这两个物种的这些实验中，将在标准化的餐食中制作PYY和生长素素，以阐明这些肠肽在我们观察到的变化中的作用。公共卫生相关性：理解介导与重量无关的抗糖尿病的机制，Roux-en-Y胃搭桥手术的影响，并鉴定出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。