Duodenal nutrient exclusion enhances glucose metabolism via CNS regulation

描述（由申请人提供）：目前使用几种减肥手术来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金标准，Roux-en-Y胃旁路术（RYGB）刺激肥胖个体的相当大的和持续的体重减轻。这种减少的肥胖通常伴随着2型糖尿病受试者的葡萄糖控制的显著改善。虽然RYGB对葡萄糖控制的一些影响继发于体重减轻，但肠道营养感测/呈递和激素谱的显著变化可能有助于许多个体的T2D的解决。越来越多的证据表明，十二指肠营养排除（DNE）可能是RYGB代谢益处的重要贡献者。我们可以直接测试这样的DNE没有胃的限制或改变摄入的营养物质的路径， 十二指肠屏障-腔内袖套（DES），防止摄入的营养物质与上肠相互作用。啮齿动物的早期临床前实验和人类的临床实验指出DES对葡萄糖稳态受损的个体的有益作用。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，这在人类中是不可能的。在我们的手中，我们观察到DES导致脂肪量减少和葡萄糖耐量明显改善，这超出了单独减肥的效果。该提案将通过高胰岛素-正常血糖钳夹来剖析葡萄糖处理的组成部分。它还将研究迷走神经和中枢神经系统在DES增强葡萄糖代谢中的作用。这些研究将共同验证这样一个假设，即十二指肠营养排除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.