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

描述（申请人提供）：胃饥饿素是一种肠道激素，刺激生长激素分泌，促进食物摄入和肥胖。生长素及其受体，生长激素分泌激素受体-1a (GHSR)，均在胰岛中表达。我们最近报道，在健康人群中，在接近生理和超生理量的胃促生长素管理减少静脉葡萄糖刺激的胰岛素分泌和损害过夜禁食后的葡萄糖耐量。相反，胃饥饿素在口服试验餐后诱导高血糖伴高胰岛素血症和胰高血糖素样肽1 （GLP-1）分泌增加。这些发现表明，在人类中，胃饥饿素对胰岛素分泌有显著影响，这些影响与胃肠道功能的其他作用相结合，并在进食和禁食状态下有所不同。目前尚不清楚胃饥饿素如何影响2型糖尿病（T2DM）患者的糖代谢。本研究的目的是研究饥饿素在健康受试者和T2DM患者中对胰岛素分泌和葡萄糖代谢的调节。此外，GHSR信号调节β细胞的机制的研究将在小鼠中进行。具体目标：1；确定胃饥饿素调节胰岛素分泌的机制。我们假设生长素对胰岛素分泌的调节需要β细胞上完整的GHSR信号传导。葡萄糖耐量和胰岛素分泌将在全球GHSR基因缺失的小鼠和仅在β细胞或仅在神经系统中存在GHSR的动物中进行比较。2. 探讨营养状况对胃饥饿素对胰岛素分泌的影响。我们假设饥饿素在禁食和进食状态下对β细胞功能有不同的影响。我们将使用顺序葡萄糖夹混合膳食方案比较空腹和进餐时的胰岛素分泌，我们之前在接受胃促生长素或生理盐水的受试者中验证过。我们还将使用GLP-1受体（GLP-1R）拮抗剂Exendin确定饥饿素刺激的GLP-1水平在这一过程中的作用（9-39）。3. 目的：探讨胃饥饿素对T2DM患者胰岛素分泌的影响。我们假设生长素会进一步损害2型糖尿病患者的β细胞功能。研究将比较T2DM患者与年龄、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，胃饥饿素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。该项目旨在了解胃饥饿素对胰岛的生理影响，并确定糖尿病患者的胰岛是否受到损害。从这个项目中获得的知识对于确定胃饥饿素系统是否可以作为治疗T2DM的药物靶点至关重要。

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.