Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery

胃肠手术后血糖改善的机制

• 批准号: 7893176
• 负责人: DAVID EUSTACE CUMMINGS
• 金额: $ 55.35万
• 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/7893176
• 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; Membrane Potentials; Messenger RNA; 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 1; glucose metabolism; glycemic control; improved; in vivo; incretin hormone; insulin secretion; insulin sensitivity; intervention effect; intravenous glucose tolerance test; islet; jejunum; mitochondrial membrane; novel; operation; protein expression; public health relevance; 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(申请人提供)：Roux-en-Y胃旁路手术导致84%的病例2型糖尿病(T2 DM)得到完全、持久的缓解，通常在手术后几天至几周内。越来越多的证据表明，这种戏剧性的现象是由那些仅与减肥和减少卡路里摄入量有关的影响造成的。RYGB的非重量依赖性抗糖尿病作用的机制尚不清楚，阐明它们可能会导致新的糖尿病药物的出现。“下肠道假说”假设RYGB通过创造一条肠道捷径，促进营养物质向远端肠道的输送，刺激类胰升糖素多肽-1，从而改善T2 DM。然而，我们和其他人发现，在大鼠中，排除近端小肠(主要是十二指肠)的一小段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“上肠假说”。这两种假说都假定了可能涉及迷走神经的机制，但迷走神经在RYGB效应中的作用尚不清楚。我们建议确定上肠道假说在人类中是否有效，并阐明其机制，以及迷走神经在RYGB降血糖效应中的作用。在RYBG之前和之后的头几周，人类将接受频繁采样的静脉葡萄糖耐量试验(FS-IVGTT)和示踪剂增强型高胰岛素/正常血糖钳夹(以测量胰岛素的分泌和敏感性)，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。相关的机制研究将在我们过去3年在胰岛素抵抗猪身上开发的一种新的长期存活RYGB模型中进行。Ossabaw猪将接受胃空肠吻合术，这种吻合术以类似于RYBG的方式(但不影响胃)增强营养物质向远端肠道的输送，无论是否将十二指肠排除在与摄入的营养物质接触之外。这两种手术都增加了远端肠道的营养刺激，都不会导致体重减轻；它们唯一的区别是有没有适度的近端肠道搭桥。这些步骤对血糖稳态的影响将通过FS-IVGTTS和最小建模来量化。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。胰岛β细胞功能和胰岛素分泌机制将在体外使用灌流的胰岛来确定。将检查不同的胃肠道节段，以确定产生相关肠肽的肠内分泌细胞的发育是否发生变化。为了研究迷走神经在RYGB效应中的作用，猪将接受这种手术，无论是否完全切断迷走神经，并将进行上述所有的死前和死后测量。血浆GLP-1、GIP水平。在这些实验中，PYY和Ghrelin将在两个物种的标准化膳食中产生，以澄清这些肠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胃旁路手术对体重非依赖性抗糖尿病影响的机制，并确定手术中影响血糖稳态的可修改组件，可能会导致糖尿病治疗中新的、更有效的治疗方法的开发。