Impact of Ghrelin of Beta-cell Function and Insulin Sensitivity in Humans

描述（由申请人提供）： 该申请旨在提供受保护的时间，以便进行以患者为导向的研究，目标是成为研究肠道激素和葡萄糖代谢的生理和药理学功能的独立研究者。Ghrelin是一种肠道激素，已被证明可以抑制胰腺β细胞胰岛素分泌并提高人体血糖水平，但尚不清楚这些是否是Ghrelin的生理功能。重要的是，人们对这种情况发生的机制知之甚少。拟议的研究旨在检验以下假设：在健康受试者中，生长激素释放肽的生理水平抑制胰岛素分泌并刺激胰高血糖素分泌，并且这是生长激素释放肽对胰岛的作用，而不是外周胰岛素敏感性改变或反调节激素（生长激素[GH]、儿茶酚胺和皮质醇）变化间接引起的作用。具体目标1：确定抑制胰岛素分泌所需的ghrelin剂量。健康人类受试者将接受三种不同剂量的胃饥饿素或盐水输注。将使用静脉内葡萄糖耐量试验评估胰岛素分泌。具体目标二：确定：a）生长素释放肽是否通过降低β-细胞对葡萄糖的敏感性来降低胰岛素释放; B）生长素释放肽是否通过降低α-细胞对葡萄糖的敏感性来增加胰高血糖素释放。在空腹血糖正常的健康受试者中，将使用频繁采样的静脉葡萄糖耐量试验和精氨酸刺激试验对β细胞和α细胞功能以及外周胰岛素敏感性进行详细评估。具体目标3：在空腹血糖正常的健康受试者中，通过使用GH受体阻滞剂、联合β-和α-肾上腺素能阻滞剂或皮质醇输注，测量反调节激素对ghrelin对胰岛素分泌和胰岛素敏感性影响的相对贡献。生长激素释放肽激动剂和生长激素释放肽拮抗剂用于治疗体重障碍的发展使得理解它们对临床相关的葡萄糖代谢的作用的机制。

DESCRIPTION (provided by applicant): This application is to provide protected time in order to perform patient oriented research with the goal of becoming an independent investigator studying the physiological and pharmacological functions of gut hormones and glucose metabolism. Ghrelin, a gut hormone, has been shown to inhibit pancreatic beta-cell insulin secretion and raise plasma glucose levels in humans, but it is unclear whether these are physiologic functions of ghrelin. Importantly, not much is known about the mechanism by which this occurs. The proposed research is designed to test the hypothesis that physiologic levels of ghrelin suppress insulin secretion and stimulate glucagon secretion in healthy human subjects and that this is an action of ghrelin on the islet, rather than one resulting indirectly from alterations in peripheral insulin sensitivity or from changes in counter-regulatory hormones (growth hormone [GH], catecholamines, and cortisol). Specific Aim 1: To determine the dose of ghrelin required to inhibit insulin secretion. Healthy human subjects will receive either ghrelin or saline infusion at three different doses. An intravenous glucose tolerance test will be used to assess insulin secretion. Specific Aim 2: To determine: a) whether ghrelin decreases insulin release by decreasing beta-cell sensitivity to glucose; b) whether ghrelin increases glucagon release by decreasing alpha-cell sensitivity to glucose. Detailed assessments of beta- and alpha-cell functions as well as peripheral insulin sensitivity will be performed using a frequently sampled intravenous glucose tolerance test and an arginine stimulation test in healthy subjects with normal fasting plasma glucose. Specific Aim 3: To measure the relative contribution of the counter-regulatory hormones to the effects of ghrelin on insulin secretion and insulin sensitivity by using either GH receptor blockade, combined beta- and alpha-adrenergic blockade, or infusion of cortisol in healthy subjects with normal fasting plasma glucose. The development of ghrelin agonists and ghrelin antagonists for treating body weight disorders makes understanding the mechanisms for their effects on glucose metabolism of clinical relevance.