Surgical Modulation of Intestinal Nutrient Transport

描述(申请人提供)：Roux-en-Y胃分流术(RYGB)是对抗日益恶化的肥胖症和2型糖尿病(T2 DM)流行的黄金标准疗法。一个令人印象深刻的观察是，T2 DM在手术后几天内迅速消失，并在任何实质性的体重减轻之前。事实上，很多专家推荐RYGB作为治疗2型糖尿病的“良方”。不幸的是，根据目前的手术指南，70%的糖尿病患者没有资格接受减肥手术。我们对RYGB导致T2 DM快速解决的观察很感兴趣，并为了帮助我们开发一种可以提供给更广泛人群的侵入性更小的方法，我们将注意力集中在这一过程对肠道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，负责大多数肠道糖的吸收，并且在T2 DM和肥胖中过度表达。有趣的是，腔内暴露于葡萄糖会导致肠道SGLT1表达的急剧而深刻的增加，这被称为肠道甜味感觉(ISS)。一些研究证实，十二指肠隔离对RYGB的成功起着关键作用，其作用机制与吸收不良无关。我们认为，通过钝化ISS，十二指肠隔离改变了剩余肠道的吸收能力，从而推迟了营养物质和胃肠激素在循环中的短暂出现。因此，RYGB后的代谢益处之所以出现，是因为营养物质的流入在没有得到阻止的情况下得到了减缓。为了开发一种侵入性更小的替代钝化ISS的方法，我们将迷走神经传入纤维作为靶点。我们假设，用辣椒素(一种自然产生的辣椒衍生物)选择性迷走神经去传入钝化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。我们将从以下几个方面对其进行测试：1.描述ISS的机制，并评估其在疾病中的失调。2.用保留迷走神经的RYGB评价十二指肠分离后ISS功能和迷走神经信号。3.研究迷走神经去传入对体重和血糖稳态的长期影响。我们认为，选择性迷走神经去传入将调节肠道SGLT1的表达和功能，并可能加强或可能取代目前用于减肥和T2 DM的外科干预措施。能够以较低的发病率复制RYGB的成功，将为许多处于危险中的个人提供巨大的好处。 公共卫生相关性：肥胖和2型糖尿病是主要的公共卫生问题，迫切需要新的治疗策略。该项目的目标是表征肠道Na+/葡萄糖转运体SGLT1的调节，并评估一种新的、侵入性较小的方法，该方法可能会复制胃旁路手术在解决肥胖和糖尿病方面的成功。

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. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes mellitus are major public health problems, to which novel therapeutic strategies are desperately needed. The goal of this project is to characterize regulation of the intestinal Na+/ glucose transporter SGLT1, and evaluate a novel and less invasive approach that may replicate the success of gastric bypass surgery in resolving obesity and diabetes.