Ghrelin was discovered as a ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin acylation is critical for GHS-R1a activation and for the endocrine effects, including stimulation of GH release and food intake. Unacylated ghrelin (UAG) is devoid of binding to GHS-R1a and endocrine activities; however, like acylated ghrelin (AG), UAG features peripheral functions, including regulation of insulin secretion and glucose metabolism. The ghrelin gene peptide Obestatin (Ob), was identified as ligand of the GPR39 and shown to counteract AG central and peripheral actions. However, these findings have been questioned and Ob physiological role remains unknown. In pancreatic islets, ghrelin localizes to apha-, beta- and ghrelin-producing epsilon-cells, suggesting specific actions in islet cell biology. Beta-cell mass and function are reduced in diabetes and interestingly, AG and UAG were found to increase survival and inhibit apoptosis of beta-cells and human islets through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms. These actions are equally exerted by small ghrelin fragments not comprising the serine 3 for acylation, suggesting the existence of different bioactive peptides. Ob, which displays similar effects, stimulates glucose-induced insulin secretion and upregulates key beta-cell regulatory genes. AG, UAG and Ob also promote glucose uptake in beta-cells and human islets, further indicating a role in glucose homeostasis. In rats, UAG and Ob, like AG, prevent STZ-induced diabetes by reducing glucose, increasing insulin levels, and preserving beta cell mass. Therefore, the ghrelin system plays a role in beta-cell survival and function, providing a new understanding and suggesting alternative therapeutic approaches in diabetes.
Beta-cell survival and function: the role of ghrelin and obestatin
GRANATA, Riccarda
2010-01-01
Abstract
Ghrelin was discovered as a ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin acylation is critical for GHS-R1a activation and for the endocrine effects, including stimulation of GH release and food intake. Unacylated ghrelin (UAG) is devoid of binding to GHS-R1a and endocrine activities; however, like acylated ghrelin (AG), UAG features peripheral functions, including regulation of insulin secretion and glucose metabolism. The ghrelin gene peptide Obestatin (Ob), was identified as ligand of the GPR39 and shown to counteract AG central and peripheral actions. However, these findings have been questioned and Ob physiological role remains unknown. In pancreatic islets, ghrelin localizes to apha-, beta- and ghrelin-producing epsilon-cells, suggesting specific actions in islet cell biology. Beta-cell mass and function are reduced in diabetes and interestingly, AG and UAG were found to increase survival and inhibit apoptosis of beta-cells and human islets through cAMP/PKA, ERK1/2- and PI3K/Akt-mediated mechanisms. These actions are equally exerted by small ghrelin fragments not comprising the serine 3 for acylation, suggesting the existence of different bioactive peptides. Ob, which displays similar effects, stimulates glucose-induced insulin secretion and upregulates key beta-cell regulatory genes. AG, UAG and Ob also promote glucose uptake in beta-cells and human islets, further indicating a role in glucose homeostasis. In rats, UAG and Ob, like AG, prevent STZ-induced diabetes by reducing glucose, increasing insulin levels, and preserving beta cell mass. Therefore, the ghrelin system plays a role in beta-cell survival and function, providing a new understanding and suggesting alternative therapeutic approaches in diabetes.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
