Neural Bases of Cephalic Phase Endocrine Responses

头期内分泌反应的神经基础

• 批准号: 10218149
• 负责人: Alan C Spector
• 金额: $ 60.78万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218149
• 关键词: Advanced Development; Animals; Assimilations; Automobile Driving; Biological Assay; Blood; Blood Glucose; Blood specimen; Body Weight; Brain; Cannulas; Catheters; Cell secretion; Cephalic; Chemicals; Chronic; Clinical; Complement; Diabetes Mellitus; Digestion; Disease; Eating; Endocrine; Enteral Nutrition; Enteroendocrine Cell; Event; Exposure to; Female; Food; Fructose; GLP-I receptor; General Population; Glucose; Head; Health; Healthy Eating; Hepatic; Hormonal; Hormones; Human; Infusion procedures; Insulin; Knowledge; L Cells; Length of Stay; Limb structure; Liquid substance; Literature; Maps; Measurement; Measures; Mediating; Metabolic; Methodology; Methods; Nerve; Neural Pathways; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Oral; Oral cavity; Outcome; Pancreas; Parenteral Nutrition; Patients; Peptides; Phase; Plasma; Play; Portal vein structure; Preparation; Procedures; Rattus; Reflex action; Reporting; Research Personnel; Role; Sampling; Signal Transduction; Site; Small Intestines; Stomach; Structure of beta Cell of islet; Sweetening Agents; Taste Perception; Techniques; Testing; Therapeutic; Therapeutic Intervention; Variant; Viral; Water; Work; absorption; base; brain circuitry; conditioning; design; experience; experimental study; feeding; glucagon-like peptide 1; insight; male; nerve transection; neural circuit; neuroinformatics; neuromechanism; neuroregulation; nutrition; optimal treatments; receptor; relating to nervous system; response; stem; sweet taste perception; taste system; therapeutic target; treatment strategy

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.

项目摘要 头相反应（CPR）是由刺激“头部”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个准备步骤 需要最佳的消化，吸收和利用的营养。虽然口后机制是 显然，为了达到这个目的，饮食期间口腔刺激对于维持正常的重要性是必不可少的 代谢功能不可低估。最广泛研究的CPR之一是 由口服葡萄糖刺激的胰岛素。然而，胰岛素CPR文献并不均衡，最有可能是因为 方法的局限性和采血点的变化。为了阐明CPRs及其潜在的神经元 我们已经开发出一种独特而敏感的大鼠制剂。它结合在一个单一的 动物口内和胃内插管，可精确输送供试品溶液，带有肝门静脉（HPV） 取样导管我们已经在雄性大鼠中使用这种制剂，发现HPV胰岛素显著早期升高， 与胃输送葡萄糖相比，口服后的GLP-1水平显着更高。Responses to 果糖或水没有表现出这样的口服/胃内差异。这些胰岛素和GLP-1增加是稳健的， 快速，在不到1分钟的时间内口服180 mg葡萄糖，3分钟内达到峰值水平。 报告了由葡萄糖经口刺激触发的显著GLP-1释放。令人印象深刻的是， 比正常进食后的量大得多。考虑到GLP-1 CPR及其 随后在血液中降解，我们将检验的一个假设是口服葡萄糖驱动的GLP-1释放是否 作为肠促胰岛素，通过迷走神经-迷走神经反射介导胰岛素CPR。 我们的设计采用了两种实验方法，组织在三个特定的目标，以揭示神经 负责这些GLP-1和胰岛素CPR的机制和回路。一种方法是使用显式控制的 口内或胃内输注葡萄糖、果糖和对照味觉溶液，随后进行HPV测量 血浆GLP-1、胰岛素和葡萄糖反应。它将测试胰岛素和GLP-1 CPR是否可以 条件，以及CPR是否在女性中重演。另一种方法将使用跨神经元病毒 追踪技术结合最先进的神经信息学方法，通过 这些味觉信号控制胰腺和肠内分泌物。此外，这两种方法都使用 功能性神经横切，以确定驱动GLP-1和胰岛素CPR的神经通路的组织。 该项目是一个由经验丰富、专业知识互补的研究人员组成的科学联盟。其 这些结果将为胰岛素和GLP-1分泌的神经控制提供新的见解。它还将定义 可以作为治疗靶点的机制，以促进需要肠内治疗的患者的治疗策略 或肠外营养，以及促进健康饮食和营养吸收的一般人群。