Neural Bases of Cephalic Phase Endocrine Responses

头期内分泌反应的神经基础

• 批准号: 10445281
• 负责人: Alan C Spector
• 金额: $ 59.59万
• 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/10445281
• 关键词: Advanced Development; Animals; 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; Neurons; 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; neural circuit; neuroinformatics; neuromechanism; neuroregulation; nutrition; optimal treatments; receptor; 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（CPRS）是由刺激“头”触发的自主和内分泌事件 受体，尤其是味觉系统的受体。这些被广泛认为是第一个准备步骤 尽管最佳的消化，滥用和利用营养需要后牙机制。 显然，对于此目的，饮食过程中口服刺激的重要性对于保持正常 不应低估代谢功能。最广泛研究的CPR之一是早期上升 口服葡萄糖刺激的胰岛素。但是，胰岛素CPR文献不平衡，很可能是因为 血液采样部位的方法论局限性和变化。阐明CPR及其基本神经如何 组织机制是组织的，我们开发了一种独特而敏感的大鼠制剂。它结合在一起 动物内部和胃内插管，可精确提供测试溶液，并具有肝门静脉（HPV） 采样导管。我们已经在雄性大鼠中使用了这种准备，以发现HPV胰岛素和 与葡萄糖的胃输送相比，口服后的GLP-1水平明显更高。对 果糖或水没有这种口腔/胃差异。这些胰岛素和GLP-1的增加是强大的， 快速，在不到1分钟内口服的3分钟内达到峰值水平。这是第一个 用葡萄糖刺激触发的明显GLP-1释放的报告。令人印象深刻的是，它的峰值是 通常比正常餐后看到的要大得多。考虑到GLP-1 CPR及其的速度 随后的血液降解，我们将测试口服葡萄糖驱动的GLP-1的假设 从肠内分泌细胞中，通过Vago-Vagal反射介导胰岛素CPR的增加。 我们的设计员工在三个特定目标中组织了两种实验方法，以揭示神经 负责这些GLP-1和胰岛素CPR的机理和电路。一种方法使用明确控制的 葡萄糖，果糖和对照味道溶液的口腔内或胃内输注，然后进行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 有条件，以及在女性中是否概括了CPR。另一种方法将使用跨神经元病毒 跟踪技术与最先进的神经信息法相结合，以通过 味道信号控制胰腺和肠内分泌分泌物。此外，两种方法都使用 功能性神经转导，以定义驱动GLP-1和胰岛素CPR的神经途径的组织。 该项目是具有完全专业知识的经验丰富的研究人员的科学联盟。 结果将为胰岛素和GLP-1分泌的神经控制提供新的见解。它也将定义 可以热针对需要进入的患者准备的治疗策略的机制 或父母的营养，并促进普通人群中更健康的饮食和营养同化。