The Role of Ghrelin to Regulate Insulin Secretion in Health and Diabetes.

生长素释放肽在健康和糖尿病中调节胰岛素分泌的作用。

基本信息

批准号：
8420680
负责人：
Jenny Tong
金额：
$ 34.15万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-25 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420680
关键词：
Affect Age American Animal Experimentation Animals Beta Cell Blood Glucose Cell physiology Cells Data Diabetes Mellitus Drug Targeting Eating Endocrine Euglycemic Clamping Fasting Functional disorder GHS-R1a Gastric Emptying Gender Gene Deletion Genetic Glucagon Glucose Glucose Clamp Goals Health Health Expenditures Homeostasis Hormones Hyperglycemia Hyperinsulinism Hypothalamic structure Individual Ingestion Insulin Intravenous Islet Cell Islets of Langerhans Knowledge Link Measures Mediating Modeling Morbidity - disease rate Mus Nervous system structure Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Pancreas Peptides Peripheral Persons Physiological Physiology Population Process Protocols documentation Regulation Reporting Research Rodent Role Saline Signal Transduction Site Somatotropin Stomach Sympathetic Nervous System System Testing Weight Work cell type diabetic energy balance feeding gastrointestinal ghrelin ghrelin receptor glucagon-like peptide glucose metabolism glucose tolerance human ghrelin impaired glucose tolerance improved in vivo insulin secretion insulin sensitivity islet knockout animal mortality mouse model non-diabetic novel nutrient metabolism pre-clinical public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): Ghrelin is a gut hormone that stimulates growth hormone secretion, promotes food intake and adiposity. Both ghrelin and its receptor, the growth hormone secretagogue receptor-1a (GHSR), are expressed in the pancreatic islets. We have recently reported that in healthy humans, ghrelin administration in near physiologic as well as supra-physiologic amounts reduces IV glucose-stimulated insulin secretion and impairs glucose tolerance after an overnight fast. In contrast, ghrelin induces hyperglycemia with hyperinsulinemia and increased glucagon-like peptide 1 (GLP-1) secretion following an orally ingested test meal. These findings indicate that in humans ghrelin has significant effects on insulin secretion and that these are integrated with other actions on GI function and vary between the fed and fasted states. It is not known how ghrelin may affect glucose metabolism in subjects with type 2 diabetes (T2DM). The objective of the current proposal is to investigate the regulation of insulin secretion and glucose metabolism by ghrelin in healthy subjects and persons with T2DM. In addition, studies of the mechanism by which GHSR signaling regulates beta cells will be performed in mice. Specific Aims: 1. To determine the mechanism by which ghrelin regulates insulin secretion. We hypothesize that ghrelin regulation of insulin secretion requires intact GHSR signaling on beta cells. Glucose tolerance and insulin secretion will be compared in mice with a global GHSR gene deletion and animals with GHSR only on beta cells or only in the nervous system. 2. To determine the role of nutrient status on ghrelin effects on insulin secretion. We hypothesize that ghrelin has differential effects on beta cell function in th fasting and fed states. We will compare insulin secretion during fasting and meal ingestion using a sequential glucose clamp-mixed meal protocol we previously validated in subjects receiving ghrelin or saline. We will also determine the role of ghrelin stimulated GLP-1 levels in this process using the GLP-1 receptor (GLP-1R) antagonist Exendin(9-39). 3. To determine the effects of ghrelin on insulin secretion in T2DM. We hypothesize that ghrelin will further impair beta cell function in subjects with type 2 diabetes. Insulin secretion and insulin action will be compared in subjects with T2DM and in their age-, gender- and weight-matched nondiabetic controls. Emerging evidence suggests that ghrelin is a key component of the regulatory system linking energy balance with nutrient metabolism. Our recent findings suggest that one aspect of this regulation is mediated through insulin secretion. This project seeks to understand the physiology of ghrelin's effect on the islet and determine whether it is compromised in individuals with diabetes. The knowledge gained from this project will be pivotal in determining whether the ghrelin system can be used as a drug target for the treatment of T2DM.

描述（由申请人提供）：生长素释放肽是一种肠道激素，可刺激生长激素分泌，促进食物摄入和肥胖。生长素释放肽及其受体生长激素促分泌素受体 1a (GHSR) 均在胰岛中表达。我们最近报道，在健康人类中，接近生理量和超生理量的生长素释放肽会减少静脉注射葡萄糖刺激的胰岛素分泌，并在禁食过夜后损害葡萄糖耐量。相比之下，胃饥饿素在口服测试餐后会诱发高血糖并伴有高胰岛素血症，并增加胰高血糖素样肽 1 (GLP-1) 的分泌。这些发现表明，在人类中，生长素释放肽对胰岛素分泌具有显着影响，并且这些影响与对胃肠道功能的其他作用相结合，并且在进食和禁食状态之间存在差异。目前尚不清楚生长素释放肽如何影响 2 型糖尿病 (T2DM) 受试者的葡萄糖代谢。当前提案的目的是研究健康受试者和 T2DM 患者中生长素释放肽对胰岛素分泌和葡萄糖代谢的调节。此外，还将在小鼠中进行 GHSR 信号调节 β 细胞机制的研究。具体目标： 1. 确定ghrelin调节胰岛素分泌的机制。我们假设 ghrelin 对胰岛素分泌的调节需要 β 细胞上完整的 GHSR 信号传导。将比较具有整体 GHSR 基因缺失的小鼠和仅在 β 细胞或仅在神经系统中具有 GHSR 的动物的葡萄糖耐量和胰岛素分泌。 2. 确定营养状况对生长素释放肽对胰岛素分泌的影响。我们假设生长素释放肽在禁食和进食状态下对 β 细胞功能有不同的影响。我们将使用我们之前在接受生长素释放肽或盐水的受试者中验证的连续葡萄糖钳混合膳食方案来比较禁食和膳食摄入期间的胰岛素分泌。我们还将使用 GLP-1 受体 (GLP-1R) 拮抗剂 Exendin(9-39) 确定生长素释放肽刺激的 GLP-1 水平在此过程中的作用。 3. 确定ghrelin对T2DM胰岛素分泌的影响。我们假设生长素释放肽会进一步损害 2 型糖尿病患者的 β 细胞功能。将比较 T2DM 受试者及其年龄、性别和体重匹配的非糖尿病对照者的胰岛素分泌和胰岛素作用。新的证据表明，生长素释放肽是连接能量平衡与营养代谢的调节系统的关键组成部分。我们最近的研究结果表明，这种调节的一方面是通过胰岛素分泌介导的。该项目旨在了解生长素释放肽对胰岛的影响的生理学，并确定其在糖尿病患者中是否受到损害。从该项目中获得的知识对于确定 ghrelin 系统是否可以用作治疗 T2DM 的药物靶点至关重要。