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

生长素释放肽对人类 β 细胞功能和胰岛素敏感性的影响

• 批准号: 8122349
• 负责人: Jenny Tong
• 金额: $ 17.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122349
• 关键词: Acute; Adrenergic Agents; Affect; Agonist; Alpha Cell; Animals; Arginine; Beta Cell; Body Weight; Catecholamines; Cell Line; Cell physiology; Cells; Clinical; Consensus; Development; Disease; Dose; Eating; Enteral; Epinephrine; Gastrointestinal Motility; Glucagon; Glucose; Goals; Growth Hormone Receptor; Hormones; Human; Hydrocortisone; In Vitro; Infusion procedures; Injection of therapeutic agent; Insulin; Intravenous; Islets of Langerhans; Measures; Pancreas; Peptides; Peripheral; Physiological; Plasma; Rattus; Regulation; Relative (related person); Research; Research Personnel; Saline; Sampling; Secretory Cell; Somatotropin; Structure of beta Cell of islet; Testing; Time; adrenergic; blood glucose regulation; clinically relevant; design; falls; fasting plasma glucose; ghrelin; ghrelin receptor; glucose metabolism; human subject; increased appetite; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; motility disorder; obesity treatment; patient oriented research; receptor; wasting; Acute; Adrenergic Agents; Affect; Agonist; Alpha Cell; Animals; Arginine; Beta Cell; Body Weight; Catecholamines; Cell Line; Cell physiology; Cells; Clinical; Consensus; Development; Disease; Dose; Eating; Enteral; Epinephrine; Gastrointestinal Motility; Glucagon; Glucose; Goals; Growth Hormone Receptor; Hormones; Human; Hydrocortisone; In Vitro; Infusion procedures; Injection of therapeutic agent; Insulin; Intravenous; Islets of Langerhans; Measures; Pancreas; Peptides; Peripheral; Physiological; Plasma; Rattus; Regulation; Relative (related person); Research; Research Personnel; Saline; Sampling; Secretory Cell; Somatotropin; Structure of beta Cell of islet; Testing; Time; adrenergic; blood glucose regulation; clinically relevant; design; falls; fasting plasma glucose; ghrelin; ghrelin receptor; glucose metabolism; human subject; increased appetite; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; motility disorder; obesity treatment; patient oriented research; receptor; wasting

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.

描述（由申请人提供）： 该应用是为了提供受保护的时间以进行以患者为导向的研究，目的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类血浆葡萄糖水平，但尚不清楚这些是否是生长素的生理功能。重要的是，关于这种情况的机制知之甚少。 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).特定目的1：确定抑制胰岛素分泌所需的剂量的剂量。健康的人类受试者将以三种不同剂量的剂量接受生长素蛋白或盐水输注。静脉注射葡萄糖耐量测试将用于评估胰岛素分泌。特定目标2：确定：a）生长素蛋白是否通过降低β细胞对葡萄糖的敏感性来降低胰岛素的释放； b）生长素是否通过降低α细胞对葡萄糖的敏感性来增加胰高血糖素的释放。将使用经常采样的静脉内葡萄糖耐受性测试和在正常禁食血浆葡萄糖的健康受试者中对β-和α细胞功能以及周围胰岛素敏感性的详细评估以及周围胰岛素敏感性。具体目的3：通过使用GH受体阻滞，β-和α-肾上腺素的联合阻断或健康受试者在健康受试者中使用正常的小吃血浆葡萄糖在健康受试者中，相对调节激素对生长素蛋白对胰岛素分泌和胰岛素敏感性的相对贡献。生长素蛋白激动剂和生长素拮抗剂治疗体重疾病的发展使得了解它们对临床相关性葡萄糖代谢的影响的作用。