Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

Abstract

The ghrelin gene peptides include acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob). AG, mainly produced by the stomach, exerts its central and peripheral effects through the GH secretagogue receptor type 1a (GHS-R1a). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide, sharing with AG many effects through an unknown receptor. Ob was discovered as the G-protein-coupled receptor 39 (GPR39) ligand; however, its physiological actions remain unclear. The endocrine pancreas is necessary for glucose homeostasis maintenance. AG, UAG, and Ob are expressed in both human and rodent pancreatic islets from fetal to adult life, and the pancreas is the major source of ghrelin in the perinatal period. GHS-R1a and GPR39 expression has been shown in b-cells and islets, as well as specific binding sites for AG, UAG, and Ob. Ghrelin colocalizes with glucagon in a-islet cells, but is also uniquely expressed in 3-islet cells, suggesting a role in islet function and development. Indeed, AG, UAG, and Ob regulate insulin secretion in b-cells and isolated islets, promote b-cell proliferation and survival, inhibit b-cell and human islet cell apoptosis, and modulate the expression of genes that are essential in pancreatic islet cell biology. They even induce b-cell regeneration and prevent diabetes in streptozotocin-treated neonatal rats. The receptor(s) mediating their effects are not fully characterized, and a signaling crosstalk has been suggested. The present review summarizes the newest findings on AG, UAG, and Ob expression in pancreatic islets and the role of these peptides on b-cell development, survival, and function.

Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer

“…Although in2c-ghrelin is insulin regulated in the prostate, we failed to detect the in2c-ghrelin isoform in the pancreas itself, despite the fact that the wild-type ghrelin transcript and the ghrelin peptide are abundantly expressed in the endocrine pancreas and ghrelin appears to play an important role in glucose homoeostasis and insulin regulation (Granata et al 2010). The importance of the ghrelin axis in the regulation of blood glucose was recently illustrated in a study of the ghrelin acylation Real-time quantitative RT-PCR analysis of (A) in2-ghrelin and (B) in1-ghrelin gene expression in 22Rv1 and LNCaP prostate cancer cell lines in response to treatment with 10 nM insulin over 48 h. The housekeeping gene, ribosomal protein L32, was used as a reference for normalisation.…”

β-Cell regeneration: the pancreatic intrinsic faculty

“…Conversely, when blood glucose is low, glucagon secreted by a-cells stimulates hepatic glycogenolysis and neoglucogenesis, thereby restoring normoglycemia. Somatostatin and PP negatively regulate b-, a-and acinar cell secretion; ghrelin represses b-cell secretion [3,4].…”

Ghrelin and Insulin Secretion in Humans: Not a Tale of Two Hormones?

“…Under these conditions, potential differential modulation by AG and UAG of additional regulators of insulin secretion should be also considered, including autonomic nervous signaling (13), circulating hormones such as growth hormone and cortisol (1,6,19), and dietary carbohydrate intake as shown by Tong et al (19). Finally, the well-demonstrated positive impact of both AG and UAG on b-cell survival and proliferation, leading to enhanced b-cell mass and higher circulating insulin in streptozotocin-induced type 1 diabetes models (10,20), poses important questions; longer-term interactions between altered insulin release and beneficial changes in b-cell mass should be directly investigated during longterm modification of ghrelin profile.…”

“…Importantly, both AG and UAG also contribute to regulate b-cell function and insulin secretion (10). GHSR-1a was identified in b-cells, and ghrelin expression has been described in different cell types in pancreatic islets (11).…”

“…Indirect AG effects, including negative regulation of vagal stimulation (13), could result in additional inhibition of insulin secretion. Therefore, AG has been commonly considered an insulinostatic hormone, although it should be pointed out that reports of AG-stimulated insulin secretion are also available from experimental models (10), likely due to differences in cell lines, animal species, and hormone concentrations (10,12). Studies in humans are notably less controversial, and most of them indicate that circulating insulin is acutely reduced following bolus or continuous AG infusion (7,14,15), also at near-physiologic levels (15).…”