Ghrelin was isolated from the stomach and identified as an endogenous ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Numerous studies have demonstrated that acylated ghrelin, besides its main endocrine actions such as stimulation of GH secretion and regulation of energy balance, has a wide spectrum of peripheral activities which engage metabolic, endocrine, cardiovascular, bone and immune systems. It is now clear that also unacylated ghrelin, although unable to bind to the GHS-R1a, is a biologically active peptide, with functions mediated through an unknown receptor. In the endocrine pancreas, ghrelin has been shown to localize to α- and β-cells and to the newly identified ghrelin-producing islet ε-cells, suggesting a role in the regulation of β-cell fate and function. Accordingly, ghrelin was recently shown to prevent diabetes in streptozotocin-treated rats, by increasing β-cell mass and insulin secretion. Survival of β-cells is of major importance for maintaining normal glucose metabolism and β-cell apoptosis is a critical event in both type 1 and 2 diabetes. We recently demonstrated that both acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of β-cells and human pancreatic islets through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms. Furthermore, both peptides stimulated glucose-induced insulin secretion by β-cells. Besides ghrelin, the ghrelin gene encodes for obestatin, whose biological functions are still largely unknown. Recently, we showed that obestatin, like ghrelin, promotes proliferation and survival of β-cell lines and human pancreatic islets through mechanisms involving the ghrelin system and the glucagon-like peptide-1 receptor (GLP-1R) signaling. Indeed obestatin, similarly to GLP-1R agonists, induced insulin secretion and expression in human islets and up-regulated the mRNA of genes that are main regulators of β-cell function, survival and differentiation. Therefore, the products of the ghrelin genes, ghrelin and obestatin, appear to play a key functional and survival role within the endocrine pancreas.
03 - 07 May 2008
European Society of Endocrinology