Surgical Modulation of Intestinal Nutrient Transport

肠道营养输送的手术调节

• 批准号: 8301545
• 负责人: Ali Tavakkoli
• 金额: $ 36.44万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301545
• 关键词: Ablation; Acute; Adipose tissue; Adverse effects; Algorithms; Appearance; Attention; Blood Circulation; Body Weight decreased; Body fat; Capsaicin; Catheters; Chronic Disease; Day Surgery; Deafferentation procedure; Development; Diabetes Mellitus; Disease; Duodenum; Epidemic; Exposure to; Fiber; Gastric Bypass; Glucose; Glucose Transporter; Goals; Gold; Guidelines; Harvest; Hormones; Hour; Human; Hyperglycemia; Individual; Infusion procedures; Intestines; Lead; Left; Long-Term Effects; Magnetic Resonance Imaging; Malabsorption Syndromes; Mediating; Metabolic; Modeling; Morbidity - disease rate; Motor; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Pathway interactions; Pharmaceutical Preparations; Population; Procedures; Process; Public Health; Qualifying; Rat-1; Rattus; Regulation; Resolution; Risk; Rodent; Rodent Model; Role; Serum; Signal Transduction; Specialist; Taste Perception; Techniques; Testing; Therapeutic; Time; United States National Institutes of Health; Up-Regulation; Vagotomy; Weight; absorption; bariatric surgery; base; blood glucose regulation; cell motility; detection of nutrient; diabetic; diabetic patient; fight against; glucagon-like peptide 1; glucose sensor; glucose tolerance; glucose uptake; ileum; improved; inflammatory marker; novel; novel therapeutics; operation; oral glucose tolerance; overexpression; patient population; prevent; receptor; response; sham surgery; success; sugar; therapeutic target; weight loss intervention

DESCRIPTION (provided by applicant): Roux-en-Y gastric bypass (RYGB) is the gold standard therapy used in the fight against the worsening obesity and type 2 diabetes mellitus (T2DM) epidemics. An impressive observation has been the rapid resolution of T2DM within days of surgery and before any substantial weight loss. In fact many specialists recommend RYGB as a 'cure' for T2DM. Unfortunately 70% of diabetic patients do not qualify for weight loss surgery based on the current surgical guidelines. We have been intrigued by the observation that RYGB leads to a rapid resolution of T2DM, and to help us develop a less invasive approach that can be offered to a wider population, have focused our attention on the impact of this procedure on the intestinal Na+/glucose cotransporter SGLT1. SGLT1 is a major intestinal transporter that is responsible for most luminal sugar absorption, and is overexpressed in T2DM and obesity. Interestingly, luminal exposure to glucose leads to an acute and profound increase in intestinal SGLT1 expression, referred to as Intestinal Sweet Sensing (ISS). Several studies have confirmed a critical role for duodenal isolation to the success of RYGB, by a mechanism not related to malabsorption. We contend that duodenal isolation, by blunting ISS alters the absorptive capacity of the remaining intestine to delay the temporal appearance of nutrients and gut hormones in the circulation. Thus, the post-RYGB metabolic benefits arise because nutrient influx is slowed without being prevented. To develop a less invasive alternative to blunt ISS, we have targeted vagal afferent fibers. We hypothesize that blunting of ISS by selective vagal deafferentation with capsaicin (a naturally occurring pepper derivative) will rapidly improve glucose homeostasis, similar to RYGB, and lead to resolution of T2DM and weight loss. We will test this in the following aims: 1. Characterize the mechanism for ISS and assess its dysregulation in disease. 2. Assess ISS function and vagal signaling after duodenal isolation by vagus-sparing RYGB. 3. Study the long term effects of vagal deafferentation on weight and glucose homeostasis. We believe that selective vagal deafferentation will modulate intestinal SGLT1 expression and function, and could enhance or possibly replace current surgical interventions for weight loss and T2DM. The ability to reproduce the success of RYGB with a lower morbidity profile would provide immense benefit to numerous individuals at risk.

描述（由申请方提供）：Roux-en-Y胃旁路术（RYGB）是用于对抗日益恶化的肥胖和2型糖尿病（T2 DM）流行病的金标准疗法。一个令人印象深刻的观察结果是在手术后几天内和任何实质性体重减轻之前T2 DM的快速消退。事实上，许多专家推荐RYGB作为T2 DM的“治愈”。不幸的是，根据目前的手术指南，70%的糖尿病患者不符合减肥手术的条件。我们对RYGB导致T2 DM快速消退的观察结果很感兴趣，为了帮助我们开发一种可以提供给更广泛人群的微创方法，我们将注意力集中在该程序对肠道Na+/葡萄糖协同转运蛋白SGLT 1的影响上。SGLT 1是一种主要的肠道转运蛋白，负责大多数管腔糖吸收，在T2 DM和肥胖症中过表达。有趣的是，肠腔暴露于葡萄糖导致肠SGLT 1表达的急性和显著增加，称为肠甜味感知（ISS）。几项研究已经证实，通过与吸收不良无关的机制，十二指肠隔离对RYGB的成功具有关键作用。我们认为，十二指肠隔离，钝化ISS改变了其余的肠道的吸收能力，延迟时间出现的营养物质和肠道激素的循环。因此，RYGB后的代谢益处出现，因为营养物质流入减慢而没有被阻止。为了开发一种侵入性更小的替代方法来替代钝性ISS，我们针对迷走神经传入纤维。我们假设，通过辣椒素（一种天然存在的辣椒衍生物）选择性迷走神经传入阻滞ISS将迅速改善葡萄糖稳态，类似于RYGB，并导致T2 DM的解决和体重减轻。我们将在以下目标中对此进行测试：1。描述ISS的机制并评估其在疾病中的失调。 2.通过保留迷走神经的RYGB评估十二指肠隔离后ISS功能和迷走神经信号传导。 3.研究迷走神经传入阻滞对体重和血糖稳态的长期影响。我们认为，选择性迷走神经传入阻滞将调节肠道SGLT 1的表达和功能，并可增强或可能取代目前用于减肥和T2 DM的手术干预。以较低的发病率复制RYGB成功的能力将为许多处于风险中的个体提供巨大的益处。