Hormonal and neural control of insulin secretion following gastric bypass surgery

描述(由申请人提供)： 这项申请旨在为候选人提供学术培训、指导和受保护的时间，目标是成为一名独立的临床研究人员。Salehi博士将通过重点研究Roux-en-Y胃分流术(RYGB)后的生理变化，研究胃肠(Gl)激素和神经信号在葡萄糖代谢中的作用。据报道，RYGB可以在手术后立即逆转2型糖尿病(T2 DM)，然后再进行任何显著的减肥。此外，越来越多的患者在手术后几年被发现患有危及生命的高胰岛素低血糖。这些发现表明，RYGB程序改变了(-cell)功能的调节，以促进胰岛素的分泌。虽然RYGB改善RYGB治疗后患者的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，Gl激素分泌增加，主要是胰高血糖素样肽1(GLP-1)，可能总体上有助于胰岛素分泌增加，在低血糖患者中作用更大。然而，也有理由怀疑神经信号的变化可能会影响RYGB后胰岛细胞的功能，与Gl激素一致，因为这些患者对食物摄入的反应有更早的胰岛素峰值和更大的胰高血糖素分泌。这项拟议的研究旨在通过确定1)刺激因素(神经和Gl激素)对胰岛细胞功能的贡献以及2)胰岛细胞对生理刺激因素的反应性来探讨RYGB对胰岛素分泌的作用，包括有或没有低血糖的RYGB患者和非手术对照组。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细胞对外源性GLP-1、假感觉或口服葡萄糖摄入的反应性来实现。为了实现她的职业目标，应聘者提出了一个为期五年的培训计划，学习实验室研究方法、统计分析和胰岛细胞生理学研究方面的技能，重点是G1激素和神经调节因子的作用。她的主要赞助人在葡萄糖代谢和Gl激素方面有很高的成就，在神经信号和胰岛细胞生理学方面也是次要的赞助人。了解RYGB影响胰岛细胞功能的生理机制，包括改善葡萄糖代谢和引起低血糖综合征，可以导致开发新的T2 DM治疗方案，以及为那些出现低血糖的患者进行手术改进或药物治疗。 公共卫生相关性：由于肥胖人口急剧增加，胃旁路手术的使用率不断上升，因此更好地了解RYGB的代谢后果至关重要。该项目的结果将为应用于糖尿病治疗以及修改减肥技术以减少高危患者组低血糖的晚期并发症提供见解。

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.