Surgical Modulation of Intestinal Nutrient Transport

描述（由申请人提供）：Roux-en-Y胃旁路（RYGB）是用于对抗日益恶化的肥胖和2型糖尿病（T2DM）流行的金标准疗法。一个令人印象深刻的观察结果是，T2DM在手术后几天内和体重显著减轻之前迅速得到解决。事实上，许多专家推荐RYGB作为2型糖尿病的“治疗方法”。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。RYGB可以快速解决T2DM，这一观察结果引起了我们的兴趣，并帮助我们开发一种侵入性更小的方法，可以提供给更广泛的人群，我们将注意力集中在该手术对肠道Na+/葡萄糖共转运体SGLT1的影响上。SGLT1是一种主要的肠道转运蛋白，负责大多数肠道糖吸收，在T2DM和肥胖中过度表达。有趣的是，肠道内暴露于葡萄糖会导致肠道SGLT1表达的急性和深刻增加，称为肠道甜味感知（ISS）。几项研究证实了十二指肠隔离对RYGB成功的关键作用，其机制与吸收不良无关。我们认为，十二指肠隔离，通过钝化ISS改变其余肠道的吸收能力，延迟营养物质和肠道激素在循环中的时间出现。因此，rygb后的代谢益处出现，因为营养流入被减缓而没有被阻止。为了开发一种创伤较小的替代钝性ISS，我们以迷走神经传入纤维为目标。我们假设，通过辣椒素（一种天然辣椒衍生物）选择性迷走神经脱神经来钝化ISS，将迅速改善葡萄糖稳态，类似于RYGB，并导致T2DM的解决和体重减轻。我们将在以下目标中对此进行测试：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。3. 研究迷走神经脱神经对体重和葡萄糖稳态的长期影响。我们认为，选择性迷走神经脱神经将调节肠道SGLT1的表达和功能，并可能加强或可能取代目前的手术干预减肥和2型糖尿病。以较低的发病率重现RYGB成功的能力将为许多处于危险中的个体提供巨大的利益。

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.