The Impact of Unacylated Ghrelin on Insulin Secretion and Glucose Tolerance in Hu

描述（由申请人提供）：Tong博士的长期目标是更好地了解生长素系统对人体胰岛素分泌和葡萄糖耐量的生理功能。胃饥饿素（一种由肠道分泌的激素）的浓度在饭前升高，饭后降低。它不仅是膳食准备的重要信号，而且还影响胰腺胰岛素分泌和血糖水平。先前的研究数据表明，酰化胃饥饿素（AG）和未酰化胃饥饿素（UAG）可能对人体葡萄糖代谢有相反的影响，AG抑制胰岛素分泌，而UAG则增加胰岛素分泌。然而，由于缺乏一致和敏感的胰岛素分泌和葡萄糖耐量测量，UAG在人体葡萄糖代谢中的作用仍然知之甚少。Tong博士正在进行的k23资助的研究旨在阐明AG在调节2细胞功能方面的生理作用，并开始了解其发生的机制。Tong博士的K23研究的初步数据表明，在健康、瘦弱的个体中，AG可以减少静脉注射（IV）葡萄糖刺激的胰岛素分泌。本申请中提出的研究是K23项目的逻辑延伸，旨在验证健康个体服用UAG会增加胰岛素分泌和改善葡萄糖耐量的中心假设。tong博士还假设UAG和AG之间存在拮抗关系，即UAG的作用会被AG的共同施用所减弱。为了实现这一目标，Tong博士计划在四个不同的日子里通过静脉输注给健康个体注射人造AG、UAG、联合AG和UAG以及生理盐水（对照）。急性期胰岛素释放、外周胰岛素敏感性和葡萄糖耐量将采用一种灵敏而稳健的方法进行测量，即频繁取样的静脉葡萄糖耐量试验。这项工作将提供明确的结果，对理解胃饥饿素在人体葡萄糖代谢中的作用至关重要。此外，该项目将为ghrelin系统是否参与2型糖尿病的发病机制以及是否可能用于糖尿病患者的治疗提供重要的新见解。将这个项目添加到Tong博士的K23中描述的研究中，将使我们能够更全面地了解胃饥饿素在葡萄糖代谢中的作用，并为在未来的研究中推进这一重要领域产生更精确的假设。

DESCRIPTION (provided by applicant): Dr. Tong's long-term goal is to better understand the physiologic functions of the ghrelin system on human insulin secretion and glucose tolerance. The concentration of ghrelin, a hormone secreted from the gut, rises before meals and decreases after eating. It is not only an important signal for meal preparation, but also influences insulin secretion from the pancreas and blood glucose levels. Data collected from previous research suggests that acylated ghrelin (AG) and unacylated ghrelin (UAG), may have opposite effects on glucose metabolism in humans with AG inhibiting insulin secretion and UAG increasing it. However, due to the lack of consistent and sensitive measures of insulin secretion and glucose tolerance, the role of UAG on human glucose metabolism remains poorly understood. Dr. Tong's ongoing K23-funded studies aim to clarify the physiologic role of AG on regulating 2-cell function and begin to understand the mechanism by which this occurs. Preliminary data from Dr. Tong's K23 studies indicate that AG decreases intravenous (IV) glucose-stimulated insulin secretion in healthy, lean individuals. The research proposed in this application is a logical extension of the K23 project and aims to test the central hypothesis that UAG administration in healthy individuals will enhance insulin secretion and improve glucose tolerance. Dr.Tong also hypothesizes that an antagonistic relationship exists between UAG and AG, such that the effects of UAG will be blunted by co- administration of AG. Towards this aim, Dr. Tong plans to administer synthetic human AG, UAG, combined AG and UAG, and saline (control) via IV infusion to healthy individuals on four separate days. Acute phase insulin release, peripheral insulin sensitivity, and glucose tolerance will be measured using a sensitive and robust method, the frequently sampled IV glucose tolerance test. This proposed work will provide definitive results that are critical for the understanding of the role of ghrelin in human glucose metabolism. Moreover, this project will provide important new insights as to whether the ghrelin system is involved in the pathogenesis of type-2 diabetes and whether it might be utilized in treating diabetic patients. Addition of this project to the studies described in Dr. Tong's K23 will allow the development of a more complete picture of the role of ghrelin in glucose metabolism, and generate more refined hypotheses for advancing this important area through future studies. PUBLIC HEALTH RELEVANCE: The gut hormone ghrelin is known to be important for the regulation of food intake and energy balance but the specific role its two molecular forms, acylated and unacylated ghrelin, in glucose homeostasis is less well defined. The goal of this project is to clarify whether unacylated ghrelin has not only an independent effect on insulin secretion and glucose tolerance but also counterbalancing actions with respect to acylated ghrelin in healthy human subjects. The knowledge to be gained from this proposed research will be significant both in advancing our understanding of the role of the ghrelin system in human glucose metabolism and in generating a foundation for the development of novel ghrelin-based therapy for the treatment of metabolic diseases.