Ghrelin is a gut hormone, initially identified as the endogenous ligand of the growth hormone secretagogue receptor (GHS-R)1a. Ghrelin acylation by ghrelin O-acyl transferase on the third serine residue, is critical for GHS-R1a activation and for the ghrelin endocrine effects, including stimulation of GH release, promotion of food intake and adiposity. Besides central effects, acylated ghrelin features many peripheral activities which engage metabolic, endocrine, cardiovascular, reproductive and immune systems. Unacylated ghrelin, although unable to bind the GHS-R1a, is biologically active, exerting positive effects on insulin secretion and glucose metabolism, by binding to a yet unknown receptor. The new ghrelin gene product obestatin, was identified as the G-protein coupled receptor 39 (GPR39) ligand and found to reduce food intake and body weight, and to counteract many central and peripheral effects of ghrelin. However, these findings, as well as binding to GPR39, have lately been questioned and obestatin physiological functions are still unclear. In the pancreatic islet, ghrelin localizes in α-cells, β-cells and in ghrelin-producing ε-cells, suggesting specific actions in islet cell fate and function. It is well known that β-cell survival is essential for maintaining glucose metabolism, and β-cell apoptosis is a critical event in both type 1 and 2 diabetes. Both acylated and unacylated ghrelin increase survival and inhibit apoptosis of β-cells and human pancreatic islets, through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms. These actions are equally exerted by small ghrelin fragments that do not comprise serine 3 for acylation, suggesting the existence of different bioactive peptides. Like ghrelin, obestatin promotes survival of β-cells and human islets through similar mechanisms and involvement of the glucagon-like peptide-1 receptor signaling. Obestatin even increased glucose-induced insulin secretion and expression of key regulatory genes for β-cell function, survival and differentiation. Moreover, both ghrelin and obestatin promote glucose uptake in β-cells and human islets, further indicating a role in glucose homeostasis. Unacylated ghrelin and obestatin, like acylated ghrelin, prevent diabetes in STZ-treated rats, by reducing glucose, increasing plasma and pancreatic insulin levels, and preserving islet cell mass. Therefore, the ghrelin system plays a major role in pancreatic β-cell function and survival and may be considered as promising candidates for the development of novel therapeutic strategies in the cure of diabetes.
The products of the ghrelin gene and beta cell viability and function
GRANATA, Riccarda
2010-01-01
Abstract
Ghrelin is a gut hormone, initially identified as the endogenous ligand of the growth hormone secretagogue receptor (GHS-R)1a. Ghrelin acylation by ghrelin O-acyl transferase on the third serine residue, is critical for GHS-R1a activation and for the ghrelin endocrine effects, including stimulation of GH release, promotion of food intake and adiposity. Besides central effects, acylated ghrelin features many peripheral activities which engage metabolic, endocrine, cardiovascular, reproductive and immune systems. Unacylated ghrelin, although unable to bind the GHS-R1a, is biologically active, exerting positive effects on insulin secretion and glucose metabolism, by binding to a yet unknown receptor. The new ghrelin gene product obestatin, was identified as the G-protein coupled receptor 39 (GPR39) ligand and found to reduce food intake and body weight, and to counteract many central and peripheral effects of ghrelin. However, these findings, as well as binding to GPR39, have lately been questioned and obestatin physiological functions are still unclear. In the pancreatic islet, ghrelin localizes in α-cells, β-cells and in ghrelin-producing ε-cells, suggesting specific actions in islet cell fate and function. It is well known that β-cell survival is essential for maintaining glucose metabolism, and β-cell apoptosis is a critical event in both type 1 and 2 diabetes. Both acylated and unacylated ghrelin increase survival and inhibit apoptosis of β-cells and human pancreatic islets, through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms. These actions are equally exerted by small ghrelin fragments that do not comprise serine 3 for acylation, suggesting the existence of different bioactive peptides. Like ghrelin, obestatin promotes survival of β-cells and human islets through similar mechanisms and involvement of the glucagon-like peptide-1 receptor signaling. Obestatin even increased glucose-induced insulin secretion and expression of key regulatory genes for β-cell function, survival and differentiation. Moreover, both ghrelin and obestatin promote glucose uptake in β-cells and human islets, further indicating a role in glucose homeostasis. Unacylated ghrelin and obestatin, like acylated ghrelin, prevent diabetes in STZ-treated rats, by reducing glucose, increasing plasma and pancreatic insulin levels, and preserving islet cell mass. Therefore, the ghrelin system plays a major role in pancreatic β-cell function and survival and may be considered as promising candidates for the development of novel therapeutic strategies in the cure of diabetes.
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