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

非酰化生长素释放肽对胡人胰岛素分泌和糖耐量的影响

• 批准号: 7963558
• 负责人: Jenny Tong
• 金额: $ 7.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-28 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963558
• 关键词: Acute; Acylation; Adipose tissue; Animal Model; Area; Binding; Blood Circulation; Blood Glucose; Cell Line; Cell physiology; Cells; Clinical; Data; Development; Dose; Eating; Endocrine; Equilibrium; Family suidae; Fasting; Food Intake Regulation; Foundations; Funding; Future; Generations; Glucose; Goals; Hepatocyte; Hormones; Human; Individual; Insulin; Insulin Resistance; Intravenous; Intravenous infusion procedures; Islet Cell; Islets of Langerhans; Knowledge; Measures; Metabolic; Metabolic Diseases; Methodology; Methods; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathogenesis; Peptides; Peripheral; Phase; Physiological; Plasma; Preparation; Rattus; Regulation; Research; Research Personnel; Rodent; Role; Saline; Sampling; Serine; Signal Transduction; Stomach; System; Testing; Therapeutic; Therapeutic Uses; Work; Writing; acyl group; base; blood glucose regulation; career development; des-n-octanoyl ghrelin; design; diabetic patient; energy balance; ghrelin; glucose metabolism; glucose output; glucose tolerance; growth hormone secretagogue receptor; human subject; improved; innovation; insight; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; novel; paracrine; public health relevance; receptor; response

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.

描述（申请人提供）：童博士的长期目标是更好地了解生长素释放肽系统对人胰岛素分泌和糖耐量的生理功能。胃饥饿素（一种从肠道分泌的激素）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，而且影响胰腺的胰岛素分泌和血糖水平。先前研究收集的数据表明，酰化生长素释放肽 (AG) 和非酰化生长素释放肽 (UAG) 可能对人体葡萄糖代谢产生相反的影响，AG 抑制胰岛素分泌，UAG 增加胰岛素分泌。然而，由于缺乏一致且灵敏的胰岛素分泌和葡萄糖耐量测量方法，UAG 对人体葡萄糖代谢的作用仍知之甚少。 Tong 博士正在进行的由 K23 资助的研究旨在阐明 AG 在调节 2 细胞功能中的生理作用，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，AG 可以减少健康、瘦人体内静脉 (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。 Tong博士还假设UAG和AG之间存在拮抗关系，因此联合施用AG会减弱UAG的作用。为了实现这一目标，Tong 博士计划在四天内通过静脉注射向健康个体施用合成人 AG、UAG、组合 AG 和 UAG 以及盐水（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使用敏感且稳健的方法（频繁采样的静脉内葡萄糖耐量试验）进行测量。这项拟议的工作将提供明确的结果，对于理解生长素释放肽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是否可用于治疗糖尿病患者提供重要的新见解。将该项目添加到 Tong 博士的 K23 中描述的研究中，将使人们更全面地了解生长素释放肽在葡萄糖代谢中的作用，并产生更精细的假设，以通过未来的研究推进这一重要领域。 公共健康相关性：众所周知，肠道激素生长素释放肽对于调节食物摄入和能量平衡很重要，但其两种分子形式（酰化和非酰化生长素释放肽）在葡萄糖稳态中的具体作用尚不清楚。该项目的目标是阐明在健康人类受试者中，未酰化的生长素释放肽是否不仅对胰岛素分泌和葡萄糖耐量具有独立的影响，而且还具有与酰化的生长素释放肽的平衡作用。从这项拟议的研究中获得的知识对于增进我们对生长素释放肽系统在人类葡萄糖代谢中的作用的理解以及为开发基于生长素释放肽的新型代谢疾病疗法奠定基础具有重要意义。