Hormonal and neural control of insulin secretion following gastric bypass surgery

描述（由申请人提供）： 这个应用程序是为候选人提供学术培训，指导和保护时间，目标是成为一名独立的临床研究人员。Salehi博士将研究胃肠（GI）激素和神经信号在葡萄糖代谢中的功能，重点是Roux-en-Y胃旁路（RYGB）后的生理变化。据报道，RYGB可以在手术后立即逆转2型糖尿病（T2 DM），然后再进行任何显着的体重减轻。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血症性低血糖。这些发现表明RYGB过程改变了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，GI激素（主要是胰高血糖素样肽I（GLP-1））的分泌增加可能有助于总体上增强胰岛素分泌，并且在患有低血糖症的患者中更大程度上增强胰岛素分泌。然而，也有理由怀疑在RYGB后神经信号传导的变化可能与GI激素一起影响胰岛细胞功能，因为这些患者响应于食物摄取具有更早的胰岛素峰值和更大的胰高血糖素分泌。所提出的研究旨在通过确定1）刺激因子（神经和GI激素）对胰岛细胞功能的贡献;和2）在具有和不具有低血糖症的RYGB患者和非手术对照中的胰岛细胞对生理刺激因子的反应性来解决RYGB对胰岛素分泌的作用。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、假进食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，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学研究的技能，重点是GI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GI激素方面的高度成就的研究者，以及神经信号传导和胰岛细胞生理学方面的次要赞助商。了解RYGB影响胰岛细胞功能的生理机制，既改善葡萄糖代谢，又引起低血糖综合征，可以为T2 DM开发新的治疗选择，以及为发生低血糖的患者开发手术改进或药物治疗。 公共卫生相关性：更好地了解RYGB的代谢后果是至关重要的，因为由于肥胖人口的急剧增加，胃旁路手术的使用越来越多。该项目的结果将提供适用于糖尿病治疗的见解以及减肥技术的修改，以减少风险患者群体中低血糖的晚期并发症。

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.