Endocrine Abstracts (2008) 16 S7.2

Ghrelin and the endocrine pancreas

Riccarda Granata

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.

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.

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