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

描述(由申请人提供)： 这项应用是为了提供保护时间，以便进行以患者为中心的研究，目标是成为研究肠道激素和葡萄糖代谢的生理和药理功能的独立调查者。Ghrelin是一种胃肠激素，已被证明可以抑制人类胰岛β细胞胰岛素的分泌，并提高血糖水平，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。这项拟议的研究旨在检验这样一种假设：在健康的受试者中，生理水平的Ghrelin抑制胰岛素分泌并刺激胰升糖素的分泌，这是Ghrelin对胰岛的作用，而不是由于外周胰岛素敏感性的变化或逆调节激素(生长激素、儿茶酚胺和皮质醇)的变化间接导致的。具体目的1：确定抑制胰岛素分泌所需的Ghrelin剂量。健康的受试者将接受三种不同剂量的Ghrelin或生理盐水输注。静脉葡萄糖耐量试验将用于评估胰岛素的分泌。具体目标2：确定：a)ghrelin是否通过降低β细胞对葡萄糖的敏感性来减少胰岛素的释放；b)ghrelin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的释放。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、联合使用β-和α-肾上腺素能阻滞剂或皮质醇，来测量反调节激素对Ghrelin影响胰岛素分泌和胰岛素敏感性的相对贡献。Ghrelin激动剂和Ghrelin拮抗剂用于治疗体重障碍的发展使得理解它们对糖代谢的影响的机制具有临床意义。

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.