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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：
9213368
负责人：
Jenny Tong
金额：
$ 34.58万
依托单位：
DUKE UNIVERSITY
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9213368
关键词：
Affect Age American Animal Experimentation Animals Beta Cell Blood Glucose Cell physiology Cells Closure by clamp Cultured Cells Data Diabetes Mellitus Eating Endocrine Euglycemic Clamping Fasting Functional disorder GHS-R1a GLP-I receptor Gastric Emptying Gender Gene Deletion Genetic Glucagon Glucose Glucose Clamp Goals Health Health Expenditures Homeostasis Hormones Human Hyperglycemia Hyperinsulinism Hypothalamic structure Impairment Individual Ingestion Insulin Intravenous Islets of Langerhans Knowledge Link Measures Mediating Modeling Morbidity - disease rate Mus Nervous system structure Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Oral 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 gastrointestinal ghrelin ghrelin receptor glucagon-like peptide 1 glucose metabolism glucose tolerance 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 relating to nervous system targeted treatment

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）：Ghrelin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。生长激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，在健康人中，近生理以及超生理量的ghrelin给药减少了IV葡萄糖刺激的胰岛素分泌，并在过夜禁食后损害葡萄糖耐量。相比之下，胃饥饿素在口服试验餐后诱导高血糖症伴高胰岛素血症，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，生长激素释放肽对胰岛素分泌具有显著影响，并且这些作用与对GI功能的其他作用相结合，并且在进食和禁食状态之间变化。尚不清楚生长激素释放肽如何影响2型糖尿病（T2 DM）受试者的葡萄糖代谢。当前提案的目的是研究生长激素释放肽对健康受试者和T2 DM患者胰岛素分泌和葡萄糖代谢的调节。此外，将在小鼠中进行GHSR信号调节β细胞的机制研究。具体目标：1。确定胃饥饿素调节胰岛素分泌的机制。我们假设生长激素释放肽调节胰岛素分泌需要β细胞上完整的GHSR信号。将在具有整体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的动物中比较葡萄糖耐量和胰岛素分泌。2.确定营养状况对ghrelin影响胰岛素分泌的作用。我们假设饥饿素在空腹和进食状态下对β细胞功能有不同的影响。我们将比较空腹和进餐时的胰岛素分泌，使用我们先前在接受生长激素释放肽或生理盐水的受试者中验证的顺序葡萄糖钳夹混合餐方案。我们还将使用GLP-1受体（GLP-1 R）拮抗剂Exendin（9-39）确定生长素释放肽刺激的GLP-1水平在该过程中的作用。3.探讨Ghrelin对2型糖尿病胰岛素分泌的影响。我们假设饥饿素将进一步损害2型糖尿病受试者的β细胞功能。将在T2 DM受试者及其年龄、性别和体重匹配的非糖尿病对照中比较胰岛素分泌和胰岛素作用。新出现的证据表明，生长激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，这种调节的一个方面是通过胰岛素分泌介导的。该项目旨在了解生长激素释放肽对胰岛的生理作用，并确定它是否在糖尿病患者中受到损害。从该项目中获得的知识将是决定ghrelin系统是否可用作治疗T2 DM的药物靶点的关键。