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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK080081-05
Application #
8122349
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2007-09-25
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$176,779
Indirect Cost
Name
University of Cincinnati
Department
Administration
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Tong, Jenny; Davis, Harold W; Gastaldelli, Amalia et al. (2016) Ghrelin Impairs Prandial Glucose Tolerance and Insulin Secretion in Healthy Humans Despite Increasing GLP-1. J Clin Endocrinol Metab 101:2405-14
Tong, Jenny; Davis, Harold W; Summer, Suzanne et al. (2014) Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans. Diabetes 63:2309-19
Tong, Jenny; Prigeon, Ronald L; Davis, Harold W et al. (2013) Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans. J Clin Endocrinol Metab 98:2536-43
Tong, Jenny; Dave, Nimita; Mugundu, Ganesh M et al. (2013) The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. Eur J Endocrinol 168:821-8
Tong, Jenny; D'Alessio, David; Ramisch, Juliane et al. (2012) Ghrelin stimulation of growth hormone isoforms: parallel secretion of total and 20-kDa growth hormone and relation to insulin sensitivity in healthy humans. J Clin Endocrinol Metab 97:3366-74
Wiedmer, Petra; Strasser, Florian; Horvath, Tamas L et al. (2011) Ghrelin-induced hypothermia: a physiological basis but no clinical risk. Physiol Behav 105:43-51
Nohara, Kazunari; Zhang, Yan; Waraich, Rizwana S et al. (2011) Early-life exposure to testosterone programs the hypothalamic melanocortin system. Endocrinology 152:1661-9
Tong, Jenny; Mannea, Erica; Aime, Pascaline et al. (2011) Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans. J Neurosci 31:5841-6
Heppner, Kristy M; Tong, Jenny; Kirchner, Henriette et al. (2011) The ghrelin O-acyltransferase-ghrelin system: a novel regulator of glucose metabolism. Curr Opin Endocrinol Diabetes Obes 18:50-5
Tong, Jenny; D'Alessio, David (2011) Eating disorders and gastrointestinal peptides. Curr Opin Endocrinol Diabetes Obes 18:42-9

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