Neural Bases of Cephalic Phase Endocrine Responses

项目总结 头相反应(CPR)是由刺激“头”引起的自主神经和内分泌事件。 感受器，尤其是味觉系统的感受器这些被广泛认为是第一步准备工作。 营养物质的最佳消化、吸收和利用所必需的。尽管后遗症机制是 显然，在进食过程中口腔刺激对维持正常的重要性是必不可少的 代谢功能不应被低估。研究最广泛的CPR之一是 由口服葡萄糖刺激的胰岛素。然而，胰岛素心肺复苏文献参差不齐，很可能是因为 血样采样点的方法限制和变异。为了阐明CPR及其潜在的神经如何 机制是有组织的，我们开发了一种独特而敏感的大鼠制剂。它结合在一个单一的 带有肝门静脉(HPV)的精确输送测试溶液的动物口腔和胃内插管 取样导管。我们在雄性大鼠身上使用了这种制剂，发现HPV胰岛素和HPV胰岛素显著提前上升 口服后GLP-1水平显著高于口服葡萄糖。对以下问题的回应 果糖或水没有表现出这样的口服/胃部差异。这些胰岛素和GLP-1的增加是强劲的 在不到1分钟的时间内口服180毫克葡萄糖后，迅速在3分钟内达到峰值。这是第一次 口服葡萄糖刺激引起GLP-1显著释放的报告。令人印象深刻的是，它的巅峰是 比正常用餐后看到的要大得多。考虑到GLP-1 CPR和ITS的快速性 随后血液中的降解，我们将测试的一个假设是口服葡萄糖驱动的GLP-1释放 来自肠内分泌细胞作为一种胰岛素，通过迷走-迷走神经反射神经调节胰岛素心肺复苏。 我们的设计采用了两种实验方法，以三个特定的目标组织起来，以揭示神经 负责这些GLP-1和胰岛素CPR的机制和电路。一种方法使用显式控制 口腔或胃内输注葡萄糖、果糖和对照味觉溶液，然后进行HPV测量 血浆GLP-1、胰岛素和血糖反应。它将测试胰岛素和GLP-1 CPR是否可以 有条件的，以及CPR是否在女性身上重现。另一种方法将使用跨神经元病毒 追踪技术与最先进的神经信息学方法相结合，通过 这些味觉信号控制着胰腺和内分泌的分泌。此外，这两种方法都使用 功能神经横切以确定驱动GLP-1和胰岛素CPRs的神经通路的组织。 该项目是由经验丰富的研究人员组成的科学联盟，他们拥有互补的专业知识。它的 研究结果将为胰岛素和GLP-1分泌的神经控制提供新的见解。它还将定义 可通过治疗靶向促进需要肠内注射的患者的治疗策略的机制 或肠外营养，以及在普通人群中促进更健康的饮食和营养同化。

PROJECT SUMMARY Cephalic phase responses (CPRs) are autonomic and endocrine events triggered by stimulation of ‘head’ receptors, especially those of the gustatory system. These are widely considered as the first preparatory steps required for the optimal digestion, absorption, and utilization of nutrients. Although postoral mechanisms are clearly essential for this purpose, the significance of oral stimulation during eating for maintaining normal metabolic function should not be underestimated. One of the most extensively studied CPRs is the early rise in insulin that is stimulated by oral glucose. However, the insulin CPR literature is uneven, most likely because of methodological limitations and variations in blood sampling sites. To clarify how CPRs and their underlying neural mechanisms are organized we have developed a unique and sensitive rat preparation. It combines in a single animal intraoral and intragastric cannulae that precisely deliver test solutions, with a hepatic portal vein (HPV) sampling catheter. We have used this preparation in male rats to find strikingly early rises in HPV insulin and GLP-1 levels that are significantly greater after oral compared to gastric delivery of glucose. Responses to fructose or water showed no such oral/gastric differences. These insulin and GLP-1 increases were robust and rapid, reaching peak levels within 3 min of orally delivering 180 mg of glucose in less than 1 min. This is the first report of significant GLP-1 release triggered by oral stimulation with glucose. Impressively, its peak is substantially greater than that seen after a normal meal. Considering the rapidity of both the GLP-1 CPR and its subsequent degradation in blood, one hypothesis that we will test is whether oral glucose-driven GLP-1 release from enteroendocrine cells acts as an incretin that mediates the insulin CPR neurally through a vago-vagal reflex. Our design employs two experimental approaches organized in three Specific Aims to reveal the neural mechanisms and circuits responsible for these GLP-1 and insulin CPRs. One approach uses explicitly controlled intraoral or intragastric infusions of glucose, fructose, and control taste solutions followed by HPV measurements of plasma GLP-1, insulin, and glucose responses. It will test whether insulin and GLP-1 CPRs can be conditioned, and whether CPRs are recapitulated in females. The other approach will use transneuronal viral tracing techniques combined with state-of-the-art neuroinformatics methods to map the neural pathways through which gustatory signals control pancreatic and enteroendocrine secretions. Furthermore, both approaches use functional nerve transections to define the organization of the neural pathways driving GLP-1 and insulin CPRs. The project is a scientific alliance of highly experienced investigators who have complementary expertise. Its outcomes will provide new insights into the neural control of insulin and GLP-1 secretion. It will also define mechanisms that could be therapeutically targeted to facilitate treatment strategies for patients requiring enteral or parenteral nutrition, as well as promoting healthier eating and nutrient assimilation in the general population.