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

描述(申请人提供)：Ghrelin是一种肠道激素，能刺激生长激素分泌，促进食物摄取和肥胖。Ghrelin及其受体生长激素促分泌素受体-1a(GHSR)在胰岛均有表达。我们最近报道，在健康人中，在隔夜禁食后，给予接近生理和超生理剂量的Ghrelin会减少静脉注射葡萄糖刺激的胰岛素分泌，并损害葡萄糖耐量。相比之下，Ghrelin会导致高血糖和高胰岛素血症，并在口服试验餐后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，Ghrelin对胰岛素分泌有显著影响，这些作用与其他对胃肠道功能的作用相结合，并在进食和禁食状态下有所不同。目前尚不清楚Ghrelin如何影响2型糖尿病(T2 DM)患者的葡萄糖代谢。本研究的目的是研究Ghrelin对健康受试者和T2 DM患者胰岛素分泌和糖代谢的调节。此外，还将在小鼠身上研究GHSR信号调节β细胞的机制。具体目的：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。我们将比较全球GHSR基因缺失的小鼠和GHSR仅在β细胞或仅在神经系统中的动物的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Ghrelin在禁食和进食状态下对胰岛细胞功能有不同的影响。我们将使用先前在接受Ghrelin或生理盐水的受试者中验证的顺序葡萄糖钳混合餐方案来比较禁食和进食期间的胰岛素分泌。我们还将使用GLP-1受体(GLP-1R)拮抗剂Exendin(9-39)来确定ghrelin刺激的GLP-1水平在这一过程中的作用。3.观察Ghrelin对2型糖尿病患者胰岛素分泌的影响。我们假设Ghrelin将进一步损害2型糖尿病受试者的β细胞功能。将比较T2 DM患者和年龄、性别和体重匹配的非糖尿病对照组的胰岛素分泌和胰岛素作用。新出现的证据表明，Ghrelin是连接能量平衡和营养代谢的调节系统的关键组成部分。我们最近的发现表明，这种调节的一个方面是通过胰岛素分泌来调节的。这个项目试图了解Ghrelin对胰岛影响的生理学，并确定它是否在糖尿病患者中受到影响。从这个项目中获得的知识将是决定Ghrelin系统是否可以用作治疗T2 DM的药物靶点的关键。

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.