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

基本信息

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
项目类别：
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

项目摘要

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）：该应用是为了为候选人提供学术培训，指导和受保护的时间，目的是成为一名独立的临床研究人员。 Salehi博士将通过重点关注Roux-en-Y-Y胃旁路（RYGB）后的生理变化来研究胃肠道（GL）激素和神经信号传导的功能。据报道，RYGB在手术后立即逆转2型糖尿病（T2DM）。此外，越来越多的患者在手术后几年被危及生命的高胰岛素低血糖。 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但是，在低血糖的患者中，也有理由怀疑神经信号的变化可能会在RYGB后与GL激素一致，因为这些患者具有较早的胰岛素峰值，并且较大的葡萄糖分泌物是响应食物摄入的胰岛素的作用。细胞功能； 2）胰岛细胞对生理刺激因子的反应，有或没有低血糖和非手术对照的RYGB患者。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对外源GLP-1，假费或口服葡萄糖摄入的β细胞响应能力来实现。为了实现她的职业目标，候选人提出了一项为期五年的培训计划，以学习实验室研究方法，统计分析和小岛细胞生理研究的技能，重点是GL激素和神经调节因素的作用。她的主要赞助商是葡萄糖代谢和GL激素方面的高度成就，以及神经信号传导和胰岛细胞生理学的次要赞助商。理解RYGB影响胰岛功能的生理机制，改善葡萄糖代谢和引起降血糖综合征可以导致T2DM的新治疗选择以及为患者的患者开发新的治疗方法，以及患者的医疗疗法。公共卫生相关性：鉴于由于人群中肥胖的急剧增加而导致胃旁路手术的使用越来越不断增加，对RYGB的代谢后果的更好理解至关重要。该项目的结果将提供有关应用糖尿病治疗的见解，以及减肥技术的修改，以减少处于危险的患者组中低血糖的迟到。