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

描述(申请人提供)：唐博士的长期目标是更好地了解Ghrelin系统对人类胰岛素分泌和葡萄糖耐量的生理功能。胃促生长素是一种从肠道分泌的荷尔蒙，它的浓度在饭前上升，进食后下降。它不仅是准备食物的重要信号，而且还影响胰腺的胰岛素分泌和血糖水平。以往的研究数据表明，酰化胃促生长素(AG)和非酰化胃促生长素(UAG)对人的葡萄糖代谢可能有相反的影响，AG抑制胰岛素分泌，UAG促进胰岛素分泌。然而，由于缺乏对胰岛素分泌和糖耐量的一致和敏感的测量，UAG对人类葡萄糖代谢的作用仍然知之甚少。唐博士正在进行的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，并开始了解这种作用发生的机制。童博士的K23研究的初步数据表明，AG减少了健康、苗条的人静脉注射(IV)葡萄糖刺激的胰岛素分泌。这项申请中提出的研究是K23项目的合乎逻辑的扩展，旨在测试在健康个体中使用UAG将增强胰岛素分泌和改善葡萄糖耐量这一中心假设。童博士还假设，UAG和AG之间存在对抗关系，因此UAG的影响将因AG的共同管理而减弱。为了实现这一目标，唐博士计划在四个单独的日子里，通过静脉输注给健康人注射合成人类AG、UAG、联合AG和UAG，以及生理盐水(对照组)。急性期胰岛素释放、外周胰岛素敏感性和葡萄糖耐量将使用一种灵敏而可靠的方法--频繁抽样的IV葡萄糖耐量试验进行测量。这项拟议的工作将提供明确的结果，这对于理解Ghrelin在人类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它是否可能用于治疗糖尿病患者提供重要的新见解。将该项目添加到唐博士的K23中描述的研究中，将使我们能够更全面地了解Ghrelin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完善的假设。 与公共健康相关：众所周知，胃肠激素Ghrelin对调节食物摄入量和能量平衡很重要，但它的两种分子形式，即酰化和非酰化Ghrelin，在葡萄糖稳态中的具体作用还不是很清楚。该项目的目的是阐明在健康受试者中，未酰化的Ghrelin是否不仅对胰岛素分泌和葡萄糖耐量有独立的影响，而且对酰化的Ghrelin有抵消作用。从这项拟议的研究中获得的知识将对促进我们对Ghrelin系统在人类葡萄糖代谢中的作用的理解以及为开发基于Ghrelin的治疗代谢性疾病的新疗法奠定基础。

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.