Neural mechanism of glucagon-like-peptide-1 receptor-mediated nausea /malaise

胰高血糖素样肽1受体介导的恶心/不适的神经机制

• 批准号: 8229260
• 负责人: MATTHEW R HAYES
• 金额: $ 8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8229260
• 关键词: Adverse effects; Adverse event; Agonist; Amygdaloid structure; Animal Model; Animals; Antiemetics; Attention; Attenuated; Basic Science; Body Weight; Brain; Cell Nucleus; Chemicals; Chronic; Combination Drug Therapy; Consumption; Deafferentation procedure; Detection; Development; Distal; Drug Delivery Systems; Drug Exposure; Eating; FDA approved; Feedback; Fistula; Food; GLP-I receptor; Gastric Emptying; Hormones; Human; Hypothalamic structure; Incidence; Individual; Ingestion; Intake; Investigation; Kaolin; Ligands; Link; Malaise; Measures; Mediating; Mediation; Modeling; Nausea; Nausea and Vomiting; Nervous system structure; Neural Pathways; Neuraxis; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Obesity; Ondansetron; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pica Disease; Population; Receptor Activation; Reporting; Research; Rodent Model; Role; Serotonin; Site; Small Intestines; Stomach; Structure; System; Taste Perception; Techniques; United States; Visceral; Vomiting; blood glucose regulation; clay; detection of nutrient; exenatide; gastrointestinal; glucagon-like peptide; glucagon-like peptide 1; hindbrain; improved; incretin hormone; neuromechanism; novel strategies; obesity treatment; receptor; research and development; research study; response; sham feeding

DESCRIPTION (provided by applicant): The proposed research focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake and body weight. FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. It is remarkable to note, however, while nausea and/or vomiting are the major adverse events (i.e. side effect) reported in ~20-50% of T2DM patients prescribed GLP-1R agonists there is very little investigation of the mechanisms mediating the nausea/malaise and virtually no understanding of the significance of nausea/malaise in relation to GLP-1R- mediated suppression of food intake. Experiments in this proposal will examine the potential mechanisms and gastrointestinal and central nervous system (CNS) structures mediating the nausea/malaise following GLP-1R activation by examining: [1] the role of GLP-1Rs expressed on vagal afferent and CNS neurons in mediating the nausea/malaise and food intake suppression of GLP-1R agonists; [2] gastrointestinal mechanisms mediating the nausea/malaise response of GLP-1R agonists. The overall research proposed will provide a framework for development of GLP-1R-mediated treatments with reduced incidence of nausea/vomiting that can be used by a greater population of obese individuals. In addition, results may help identify potential targets for combination drug therapy to ameliorate the malaise side effects of current FDA-approved GLP-1R ligands. PUBLIC HEALTH RELEVANCE: Basic science discoveries have identified specific brain chemical systems that can reduce food intake when stimulated. While currently no pharmaceutical treatment for obesity exists, drugs targeting the hormone glucagon-like-peptide-1 (GLP-1) hold promise as food intake is suppressed following their administration. Unfortunately, nausea and/or vomiting are the major side effects of these GLP-1 drugs and therefore this proposal aims to identify the potential mechanisms and gastrointestinal and brain structures mediating the nausea of these drugs, providing necessary research for development of GLP-1 treatments for obesity with reduced incidence of nausea/vomiting.

描述（由申请人提供）：拟议的研究重点是神经肽胰高血糖素样肽-1（GLP-1）及其在控制摄食量和体重中的作用。FDA批准用于治疗II型糖尿病（T2 DM）的GLP-1受体（GLP-1 R）激动剂可改善血糖调节，此外，还可在人类和动物模型中显著降低摄食量和体重。因此，最近关注长效GLP-1 R激动剂作为肥胖症的潜在治疗。然而，值得注意的是，尽管恶心和/或呕吐是约20-50%接受GLP-1 R激动剂治疗的T2 DM患者报告的主要不良事件（即副作用），但对介导恶心/不适的机制研究很少，几乎不了解恶心/不适与GLP-1 R介导的摄食抑制相关的意义。本提案中的实验将通过检查以下内容来检查介导GLP-1 R激活后恶心/不适的潜在机制以及胃肠道和中枢神经系统（CNS）结构：[1]迷走神经传入神经和中枢神经系统神经元上表达的GLP-1 R在介导恶心/不适中的作用GLP-1 R激动剂的食物摄入抑制;[2]介导GLP-1 R激动剂恶心/不适反应的胃肠道机制。拟定的总体研究将为开发GLP-1 R介导的治疗提供框架，降低恶心/呕吐的发生率，可用于更多肥胖人群。此外，研究结果可能有助于确定联合药物治疗的潜在靶点，以改善目前FDA批准的GLP-1 R配体的不适副作用。 公共卫生相关性：基础科学发现已经确定了特定的大脑化学系统，可以在受到刺激时减少食物摄入。虽然目前还没有针对肥胖症的药物治疗，但靶向激素胰高血糖素样肽-1（GLP-1）的药物有望在给药后抑制食物摄入。不幸的是，恶心和/或呕吐是这些GLP-1药物的主要副作用，因此本提案旨在确定介导这些药物恶心的潜在机制以及胃肠道和脑结构，为开发GLP-1治疗肥胖症并降低恶心/呕吐发生率提供必要的研究。