Final Answer: Ghrelin Can Suppress Insulin Secretion in Humans, but Is It Clinically Relevant?

Ghrelin is a 28–amino acid peptide initially isolated from rat and human stomachs as an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a) (1) using an intracellular calcium influx assay on a stable cell expressing rat GHS-R. At the time of its discovery in 1999, ghrelin was known to increase growth hormone release from the pituitary gland by binding to GHS-R1a, and 1 year later, its role in food intake and body adiposity was described (2). Since then, numerous additional effects of ghrelin have been demonstrated, including regulating cell proliferation and survival, apoptosis, inflammation, angiogenesis, development and reproduction as well as metabolism. Recently, it has become of great research interest whether ghrelin also has a role in -cell function. This research area is particularly important given its potential to lead to the development of novel strategies to increase insulin secretion for the treatment of type 2 diabetes. In humans, circulating ghrelin levels surge immediately before meals and fall to a nadir within 1 h after food intake, which results in a twoto threefold variation in plasma levels. Circulating ghrelin is primarily produced in the stomach, but smaller amounts are also produced in the brain, heart, lung, kidney, placenta, gastrointestinal tract, and pancreas. Within the islets of Langerhans of the pancreas, ghrelin production has been found in -cells, -cells, and the more recently discovered ε-cells (3). Ghrelin peptides exist in two major forms, unacylated ghrelin and acylated ghrelin, and only the latter binds to GHS-R1a. Acylation is catalyzed by ghrelin O-acyltransferase (GOAT), which is, interestingly, highly expressed in the stomach and the pancreas in humans (4). Consistent with the multitude of effects of ghrelin, GHS-R1a is expressed in variety of tissues. Most importantly, with regard to insulin secretion, GHS-R1a partially colocalizes with insulin-positive -cells in human pancreatic islets (5), suggesting that human -cell might be directly responsive to ghrelin stimulation. To date, the role of ghrelin in the regulation of insulin secretion remains controversial. Perhaps because of differences in the experimental conditions, ghrelin was found to inhibit insulin secretion in the majority of studies but to stimulate insulin secretion in others. For example, ghrelin increased cytosolic free Ca concentrations in rat -cells and increased insulin secretion in isolated rat pancreatic islets under glucose-stimulated conditions (6). Furthermore, ghrelin increased insulin secretion from the pancreas of both normal and diabetic rats (7,8). In contrast, GHS-R1a blockade by specific antagonists or ghrelin inactivation using an antiserum enhanced glucose-induced insulin release and intracellular Ca concentrations in isolated rat islets (9). Further, exogenous ghrelin decreased insulin secretion in isolated mouse pancreata (10), in mouse and rat isolated islets (11), and in -cell lines (12). In humans, data regarding the effects of ghrelin on insulin secretion are scant and inconsistent. Although intravenous injection of ghrelin decreased plasma insulin and increased plasma glucose concentrations in overnightfasted humans in some studies that raised plasma ghrelin at least 4.5-fold (13,14), no changes in insulin and glucose were observed in another that raised plasma ghrelin 2to 3-fold (15). Tong et al. (16) in a recent issue of Diabetes have, therefore, revisited the effects of ghrelin on -cell function in humans using a more sensitive approach. To this end, acyl ghrelin (0.3, 0.9, or 1.5 nmol/kg/h) or saline was infused in 12 healthy, young, nonobese subjects on four separate occasions in a counterbalanced fashion after an overnight fast. After reaching steady-state plasma ghrelin levels, an intravenous glucose tolerance test was performed on each occasion to determine the acute insulin response to intravenous glucose (AIRg), the acute Cpeptide response to intravenous glucose (ACRg) as well the glucose disappearance constant as an index of intravenous glucose tolerance. The authors found that ghrelin infusion did not alter fasting insulin or glucose concentrations but significantly decreased AIRg 30–45% in a dose-dependent manner. Similar suppressions were seen in the C-peptide release in response to intravenous glucose, indicating that the ghrelin-induced reduction in plasma insulin levels was not due to increased hepatic insulin clearance. In addition, ghrelin infusion at 0.3 and 1.5 nmol/kg/h significantly decreased the glucose disappearance constant by 30%. These responses to ghrelin infusion were associated with marked and dose-dependent increases in plasma growth hormone and cortisol concentrations but unaltered plasma concentrations of glucagon, epinephrine, and norepinephrine. The authors conclude that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in humans. Moreover, they put forward that endogenous ghrelin may have a role in physiological insulin secretion and that ghrelin antagonists could improve -cell function. The findings by Tong et al. provide clear proof of concept that ghrelin can reduce glucose-stimulated insulin secretion. The experiments were logically designed, and the data are clear. However, there are at least two reasons From the Department of Endocrinology, Carl T. Hayden VA Medical Center, Phoenix, Arizona, and the Center for Metabolic Biology, Arizona State University, Tempe, Arizona. Corresponding author: Christian Meyer, [email protected]. DOI: 10.2337/db10-1088 © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, published in Diabetes 2010;59:2145–2151. COMMENTARY