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

描述（由申请人提供）：Dr. Tong的长期目标是更好地了解ghrelin系统对人胰岛素分泌和葡萄糖耐量的生理功能。胃饥饿素是一种由肠道分泌的激素，它的浓度在饭前升高，饭后降低。它不仅是膳食准备的重要信号，而且还影响胰腺的胰岛素分泌和血糖水平。以往的研究表明，酰化生长激素释放肽（AG）和非酰化生长激素释放肽（UAG）对人体葡萄糖代谢可能具有相反的作用，AG抑制胰岛素分泌，UAG增加胰岛素分泌，但由于缺乏一致和敏感的胰岛素分泌和葡萄糖耐量指标，UAG在人体葡萄糖代谢中的作用尚不清楚。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，并开始了解这种情况发生的机制。Tong博士的K23研究的初步数据表明，AG降低了健康、瘦个体的静脉（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，旨在检验健康个体中UAG给药将增强胰岛素分泌并改善葡萄糖耐量的中心假设。Dr.Tong还假设UAG和AG之间存在拮抗关系，因此UAG的作用将通过AG的联合给药而减弱。为了实现这一目标，Tong博士计划在四个不同的日子里通过IV输注向健康个体施用合成的人AG、UAG、AG和UAG组合以及生理盐水（对照）。将使用灵敏且稳健的方法（频繁采样的IV葡萄糖耐量试验）测量急性时相胰岛素释放、外周胰岛素敏感性和葡萄糖耐量。这项拟议的工作将提供明确的结果，这是至关重要的生长激素释放肽在人体葡萄糖代谢中的作用的理解。此外，该项目将提供重要的新见解，如ghrelin系统是否参与2型糖尿病的发病机制，以及它是否可以用于治疗糖尿病患者。将该项目添加到Tong博士的K23中所述的研究中，将有助于更全面地了解ghrelin在葡萄糖代谢中的作用，并通过未来的研究为推进这一重要领域产生更精确的假设。 公共卫生相关性：已知肠激素生长激素释放肽对于调节食物摄入和能量平衡是重要的，但是其两种分子形式（酰化和未酰化生长激素释放肽）在葡萄糖稳态中的具体作用不太清楚。本项目的目标是阐明非酰化生长激素释放肽是否不仅对胰岛素分泌和葡萄糖耐量具有独立作用，而且对健康受试者中酰化生长激素释放肽具有平衡作用。从这项拟议的研究中获得的知识将是重要的，无论是在推进我们的理解的ghrelin系统在人类葡萄糖代谢中的作用，并在生成一个基础，为开发新的ghrelin为基础的治疗代谢性疾病的治疗。

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.