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.
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