Hormonal and neural control of insulin secretion following gastric bypass surgery

胃绕道手术后胰岛素分泌的激素和神经控制

• 批准号: 8081759
• 负责人: Marzieh Salehi
• 金额: $ 17.77万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081759
• 关键词: Address; Affect; Area; Bariatrics; Beta Cell; Body Weight decreased; C-Peptide; Cell physiology; Cells; Clinical; Complication; Consumption; Control Groups; Development; Diabetes Mellitus; Diffuse; Distal; Dose; Endocrine; Euglycemic Clamping; Food; Gastric Bypass; Gastrointestinal Hormones; Glucagon; Glucose; Glucose Clamp; Goals; Growth; Health; Histology; Hormonal; Hormones; Hyperglycemia; Hyperinsulinism; Hyperplasia; Hypoglycemia; Individual; Ingestion; Insulin; Islet Cell; Laboratory Research; Lead; Learning; Life; Limb structure; Measures; Mediating; Medical; Mentorship; Metabolic; Modification; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Oral; Pancreas; Pancreatectomy; Pancreatic Polypeptide; Parasympathetic Nervous System; Patients; Persons; Phenotype; Physiological; Plasma; Population; Principal Investigator; Procedures; Process; Regulation; Reporting; Research; Research Methodology; Research Personnel; Resolution; Risk; Role; Signal Transduction; Small Intestines; Stimulus; Stomach; Subgroup; Syndrome; Techniques; Testing; Time; Training; Training Programs; Up-Regulation; bariatric surgery; blood glucose regulation; career; cholinergic; design; diabetic patient; gastrointestinal; glucagon-like peptide; glucose metabolism; glucose tolerance; improved; insight; insulin secretion; insulinoma; interest; islet; neural stimulation; neuroregulation; novel therapeutics; obesity treatment; receptor; relating to nervous system; response; sham feeding; skills; visceral afferent nerve

DESCRIPTION (provided by applicant): This application is to provide the candidate with scholarly training, mentorship, and protected time with the goal of becoming an independent clinical researcher. Dr. Salehi will study the functions of gastrointestinal (Gl) hormones and neural signaling in glucose metabolism by focusing on the physiologic changes following Roux-en-Y gastric bypass (RYGB). RYGB has been reported to reverse type 2 diabetes (T2DM) immediately after surgery before any significant weight loss. In addition, a growing number of patients have been recognized with life-threatening hyperinsulinemic hypoglycemia several years following their surgery. These findings suggest that the RYGB procedure alters the regulation of (-cell function to promote insulin secretion. While the mechanisms by which RYGB improves glucose metabolism or alters islet cell function in patients after RYGB are not understood, recent studies suggest that increased secretion of Gl hormones, primarily glucagon-like peptide 1 (GLP-1), may contribute to enhanced insulin secretion in general, and to a greater extent in patients with hypoglycemia. However, there is also reason to suspect that changes in neural signaling may influence islet cell function in concert with Gl hormones after RYGB, since these patients have an earlier insulin peak and a larger glucagon secretion in response to food ingestion. The proposed research is designed to address the role of RYGB on insulin secretion by determining 1) the contribution of stimulatory factors (neural and Gl hormone) on islet cell function; and 2) the islet cell responsiveness to the physiologic stimulatory factors, in RYGB patients with and without hypoglycemia and non-operated controls. The first goal will be achieved by comparing the effects of cholinergic or GLP-1 blockade on the release of postprandial islet hormones. The second goal will be accomplished by measuring beta-cell responsiveness to exogenous GLP-1, sham feeing, or oral glucose ingestion. To achieve her career objectives, the candidate proposes a five-year training program to learn skills in laboratory research methods, statistical analysis, and islet cell physiologic studies focusing on the role of Gl hormones and neural regulatory factors. Her primary sponsor is highly accomplished investigator in glucose metabolism and Gl hormones and the secondary sponsor in neural signaling and islet cell physiology. Understanding the physiologic mechanisms whereby RYGB influences islet cell function, both improving glucose metabolism and causing hypoglycemic syndrome can lead to the development of new therapeutic options for T2DM as well as surgical refinements or medical therapies for those patients who develop hypoglycemia. PUBLIC HEALTH RELEVANCE: Better understanding of metabolic consequences of RYGB is critical given the rising use of gastric bypass surgeries due to dramatic increase of obesity in the population. The results of this project will provide insights to apply to treatment of diabetes as well as modification of bariatric techniques to reduce the late-complications of hypoglycemia in the groups of patients at risk.

描述（由申请人提供）： 该申请旨在为候选人提供学术培训、指导和受保护的时间，以成为一名独立的临床研究员。 Salehi 博士将重点研究 Roux-en-Y 胃绕道手术 (RYGB) 后的生理变化，研究胃肠道 (GI) 激素和神经信号在葡萄糖代谢中的功能。据报道，RYGB 可以在手术后立即逆转 2 型糖尿病 (T2DM)，然后出现明显的体重减轻。此外，越来越多的患者在手术后几年发现患有危及生命的高胰岛素性低血糖症。这些发现表明，RYGB 程序改变了β细胞功能的调节，以促进胰岛素分泌。虽然 RYGB 改善 RYGB 后患者葡萄糖代谢或改变胰岛细胞功能的机制尚不清楚，但最近的研究表明，胰岛细胞分泌增加激素，主要是胰高血糖素样肽 1 (GLP-1)，通常可能有助于增强胰岛素分泌，并且在低血糖患者中作用更大。然而，也有理由怀疑神经信号传导的变化可能会产生影响。 RYGB 后胰岛细胞功能与胰岛激素协调一致，因为这些患者的胰岛素峰值较早，并且响应食物摄入而分泌较多胰高血糖素。本研究旨在通过确定 1) 的贡献来解决 RYGB 对胰岛素分泌的作用。刺激因子（神经和胃肠激素）对胰岛细胞功能的影响； 2) 患有或不患有低血糖的 RYGB 患者以及未手术对照的胰岛细胞对生理刺激因素的反应。第一个目标将通过比较胆碱能或 GLP-1 阻断对餐后胰岛激素释放的影响来实现。第二个目标将通过测量 β 细胞对外源 GLP-1、假喂食或口服葡萄糖摄入的反应来实现。为了实现她的职业目标，候选人提出了一个为期五年的培训计划，以学习实验室研究方法、统计分析和胰岛细胞生理研究方面的技能，重点是胃肠道激素和神经调节因子的作用。她的主要赞助商是葡萄糖代谢和胃肠激素领域卓有成就的研究者，次要赞助商是神经信号传导和胰岛细胞生理学领域的研究者。了解 RYGB 影响胰岛细胞功能、改善葡萄糖代谢和引起低血糖综合征的生理机制，可以为 T2DM 开发新的治疗方案，并为发生低血糖的患者提供手术改进或药物治疗。 公共卫生相关性：由于人口肥胖率急剧增加，胃绕道手术的使用不断增加，因此更好地了解 RYGB 的代谢后果至关重要。该项目的结果将为糖尿病治疗以及减肥技术的改进提供见解，以减少高危患者群体中低血糖的晚期并发症。