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

Abstract

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 β-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 two- to 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 α-cells, β-cells, and the more recently discovered e-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 …