Hormonal and neural control of insulin secretion following gastric bypass surgery

项目主任/首席调查员(最后、第一、中间)：Salehi，MafZJeh 项目总结(见说明)： 此应用程序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员。萨利希博士将研究胃肠道的功能 (GL)激素和神经信号在糖代谢中的作用 Roux-en-Y胃分流术(RYGB)。RYGB已被报道可逆转2型糖尿病(T2 DM) 在手术后立即进行任何显著的体重减轻。此外，越来越多的患者患有 在手术后几年，他们被认为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p细胞功能的调节，以促进胰岛素 分泌物。而RYGB改善糖代谢或改变胰岛细胞功能的机制 RYGB后的患者尚不清楚，最近的研究表明，G1激素的分泌增加， 主要是胰升糖素样肽1(GLP-1)，通常可能有助于促进胰岛素分泌，并有助于 患者发生低血糖的程度较大。然而，也有理由怀疑 神经信号可能与Gl激素一起影响RYGB后的胰岛细胞功能，因为这些 患者对食物摄入的反应有较早的胰岛素峰值和较大的胰高血糖素分泌。这个 拟议的研究旨在通过确定1)RYGB在胰岛素分泌中的作用 刺激因子(神经和Gl激素)对胰岛细胞功能的贡献；2)胰岛细胞 RYGB患者对生理刺激因素的反应性，伴或不伴低血糖和 非操作控制。第一个目标将通过比较胆碱能或GLP-1的效果来实现 阻断餐后胰岛激素的释放。第二个目标将通过测量来实现 β细胞对外源性GLP-1、假感觉或口服葡萄糖摄取的反应性。为了成就她的事业 目标，候选人提出了一个为期五年的培训计划，以学习实验室研究技能 方法、统计分析和胰岛细胞生理学研究，重点研究Gl激素和 神经调节因素。她的主要赞助人是在葡萄糖代谢方面非常有成就的研究员。 Gl激素和神经信号转导及胰岛细胞生理学的次级赞助者。了解 RYGB影响胰岛细胞功能的生理机制，均可改善糖代谢 而引起低血糖综合征可以导致T2 DM新的治疗选择的发展 以及对那些出现低血糖的患者进行手术改进或药物治疗。 相关性(请参阅说明)： 鉴于越来越多的人使用胃旁路手术，更好地理解RYGB的代谢后果至关重要 由于人口中肥胖症的急剧增加而进行的手术。该项目的结果将提供深入的见解 应用于糖尿病的治疗以及减肥技术的改进，以减少迟发- 高危人群中的低血糖并发症。

Program Director/Principal Investigator (Last, First, Middle): Salehi, MafZJeh PROJECT SUMMARY (Seeinstructions): 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 p-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. RELEVANCE (See instructions): 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.