Duodenal nutrient exclusion enhances glucose metabolism via CNS regulation

描述(申请人提供)：几种减肥手术目前用于产生持续的体重减轻和治疗肥胖相关的合并症。目前被认为是减肥外科手术的黄金标准，Roux-en-Y胃旁路手术(RYGB)可以刺激肥胖者显著和持续的体重减轻。肥胖的减少往往伴随着2型糖尿病受试者血糖控制的显著改善。虽然RYGB在血糖控制方面的一些作用是次要的，但肠道营养感知/呈现和激素谱的戏剧性变化可能有助于许多人T2D的解决。越来越多的证据表明，十二指肠营养排斥(DNE)可能是RYGB代谢益处的一个重要贡献因素。我们可以在不限制胃或改变营养摄入途径的情况下直接检测这种DNE。 十二指肠，屏障-肠内膜套(DES)，防止摄入的营养物质与上肠相互作用。早期的啮齿动物临床前试验和人类临床试验表明，DES对葡萄糖稳态受损的个体有有益效果。我们已经成功地建立了DES的啮齿动物模型，这将允许对DES进行仔细的机械测试，这在人类是不可能的。在我们的手中，我们观察到DES导致了较小的脂肪质量和明显的糖耐量改善，这超过了单独减肥的效果。这项提案将剖析通过高胰岛素-正常血糖钳夹来处理葡萄糖的组成部分。它还将研究迷走神经和中枢神经系统在葡萄糖代谢减弱中的作用。这些研究将共同检验这样一种假设，即十二指肠营养排斥恢复了这种营养感应回路调节葡萄糖稳态的能力。

DESCRIPTION (provided by applicant): Several bariatric operations are currently used to produce sustained weight loss and treat obesity- related comorbidities. Currently considered the gold standard in bariatric surgical procedures, Roux-en-Y Gastric Bypass (RYGB) stimulates a considerable and sustained weight-loss in obese individuals. This reduced adiposity is often accompanied by profound improvement in glucose control of type 2 diabetic subjects. While some of the effects of RYGB on glucose control are secondary to reduced body weight, dramatic changes in gut nutrient sensing/presentation and hormone profile may contribute to the resolution of T2D in many individuals. Accumulating evidence indicates that duodenal nutrient exclusion (DNE) may be an important contributor to the metabolic benefits of RYGB. We can directly test such DNE without gastric restriction or altering the path of ingested nutrients using duodenal, barrier-endolumenal sleeves (DES) that prevent ingested nutrients from interacting with the upper intestine. Early pre-clinical experiments in rodents and clinical experiments in humans point to beneficial effects of DES in individuals with impaired glucose homeostasis. We have successfully established a rodent model of a DES that will allow for the careful mechanistic testing of DES that is not possible in humans. In our hands, we observe that DES results in a small in fat mass and a clear improvement in glucose tolerance, which is above and beyond the effect of the weight loss alone. This proposal will dissect components of glucose handling via hyperinsulinemic-euglycemic clamps. It will also investigate the role of the vagus and the central nervous system in the DES-enhancement of glucose metabolism. Together these studies will test the hypothesis that duodenal nutrient exclusion restores the ability of this nutrient-sensing circuitry to regulate glucose homeostasis.