Ghrelin was identified in the stomach as endogenous ligand of the growth hormone secretagogue receptor (GHS-R)1a. Acylated ghrelin (AG), through interaction with GHS-R1a, exerts a wide range of central and peripheral effects, including regulation of GH secretion, cardiovascular and metabolic functions, cell growth and survival. Unacylated ghrelin (UAG), although unable to bind GHS-R1a, shows pleiotropic effects, mediated by a yet unknown receptor. Obestatin, a recently discovered ghrelin gene product, exerts biological functions that are similar or opposed to those of ghrelin; however, many effects, as well as binding to its putative receptor GPR39, have been debated. In the endocrine pancreas, ghrelin localizes to α- and β-cells and to ghrelin-producing ε-cells, suggesting a role in regulation of β-cell fate and function. Indeed, AG was found to prevent diabetes in streptozotocin (STZ)-treated rats, by increasing β-cell mass and insulin secretion. β-cell survival is essential for maintaining glucose metabolism, and β-cell apoptosis is a critical event in both type 1 and 2 diabetes. Recently, we demonstrated that AG and UAG increase proliferation and inhibit apoptosis of β-cells and human pancreatic islets through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms, and stimulate insulin secretion from β-cells. Interestingly, small UAG fragments were also found to exert insulinotropic, survival and antiapoptotic effects in β-cells and human islets, suggesting that UAG biological activity is not restricted to the entire peptide. Obestatin, like ghrelin, promotes proliferation and survival of β-cells and human islets through involvement of the ghrelin system and the glucagon-like peptide-1 receptor signaling (GLP-1R). Similarly to GLP-1R agonists, obestatin promotes insulin secretion and expression and up-regulates the mRNA of genes that are essential for β-cell function, survival and differentiation. AG, UAG and obestatin even increase glucose uptake in β-cells and human islets, further suggesting a regulatory role in glucose homeostasis. Moreover, besides AG, also UAG and obestatin prevent diabetes in STZ-treated newborn rats, by reducing plasma glucose and increasing pancreatic insulin and islet cell mass. Thus, our findings, together with previous studies, provide further evidence that the ghrelin system, through complex signaling mechanisms and interactions, plays an important role in the regulation of pancreatic islet function and β-cell survival.

Ghrelin Analogs & Islet Function

GRANATA, Riccarda
2009-01-01

Abstract

Ghrelin was identified in the stomach as endogenous ligand of the growth hormone secretagogue receptor (GHS-R)1a. Acylated ghrelin (AG), through interaction with GHS-R1a, exerts a wide range of central and peripheral effects, including regulation of GH secretion, cardiovascular and metabolic functions, cell growth and survival. Unacylated ghrelin (UAG), although unable to bind GHS-R1a, shows pleiotropic effects, mediated by a yet unknown receptor. Obestatin, a recently discovered ghrelin gene product, exerts biological functions that are similar or opposed to those of ghrelin; however, many effects, as well as binding to its putative receptor GPR39, have been debated. In the endocrine pancreas, ghrelin localizes to α- and β-cells and to ghrelin-producing ε-cells, suggesting a role in regulation of β-cell fate and function. Indeed, AG was found to prevent diabetes in streptozotocin (STZ)-treated rats, by increasing β-cell mass and insulin secretion. β-cell survival is essential for maintaining glucose metabolism, and β-cell apoptosis is a critical event in both type 1 and 2 diabetes. Recently, we demonstrated that AG and UAG increase proliferation and inhibit apoptosis of β-cells and human pancreatic islets through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms, and stimulate insulin secretion from β-cells. Interestingly, small UAG fragments were also found to exert insulinotropic, survival and antiapoptotic effects in β-cells and human islets, suggesting that UAG biological activity is not restricted to the entire peptide. Obestatin, like ghrelin, promotes proliferation and survival of β-cells and human islets through involvement of the ghrelin system and the glucagon-like peptide-1 receptor signaling (GLP-1R). Similarly to GLP-1R agonists, obestatin promotes insulin secretion and expression and up-regulates the mRNA of genes that are essential for β-cell function, survival and differentiation. AG, UAG and obestatin even increase glucose uptake in β-cells and human islets, further suggesting a regulatory role in glucose homeostasis. Moreover, besides AG, also UAG and obestatin prevent diabetes in STZ-treated newborn rats, by reducing plasma glucose and increasing pancreatic insulin and islet cell mass. Thus, our findings, together with previous studies, provide further evidence that the ghrelin system, through complex signaling mechanisms and interactions, plays an important role in the regulation of pancreatic islet function and β-cell survival.
2009
The Endocrine Society's 91st Annual Meeting
Washington DC, USA
June 10-13, 2009
Endocrine Society Abstract
The Endocrine Society's 91st Annual Meeting, Washington DC 2009, June 10-13, 2009
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http://www.endo-society.org/endo09/
Riccarda Granata
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/75522
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