The 28-aminoacid peptide unacylated ghrelin (UAG), although unable to bind the acylated ghrelin (AG) receptor GHS-R1a, exerts many biological effects. UAG, similarly to AG, protects in vitro β-cells and human pancreatic islets against apoptosis, stimulates their proliferation and enhances glucose-induced insulin secretion at physiological concentrations. In vivo, UAG prevents diabetes at adult age in streptozotocin (STZ)-treated neonatal rats by reducing blood glucose, and increasing β-cell mass and insulin secretion. Based on these evidence, we investigated the potential survival effects of UAG fragments in HIT-T15 β-cells and human pancreatic islet cells. These fragments either included or excluded serine-3, the site for ghrelin octanoylation essential for GHS-R1a binding. UAG fragment comprising aminoacids 6-13 displayed survival and antiapoptotic actions equal to or even greater than full length UAG (1-28). Moreover, although to a lesser extent, fragments 1-14 and 1-18 retained all the effects of UAG 1-28, including stimulation of glucose-induced insulin secretion. Conversely, fragments 8-13, 8-12 and, particularly, 1-5 and 17-28, showed reduced or no activity. Notably, UAG(6-13), which showed the best protective effects in vitro, also prevented diabetes at adult age in STZ-treated neonatal rats, by decreasing blood glucose and increasing blood and pancreatic insulin levels, similarly to UAG. These findings indicate that UAG fragments, similarly to the full length peptide, exert protective effects in β-cells and human islets. The strong UAG(6-13)-induced survival action suggests that this fragment may be sufficient per se to display the protective effects of UAG, without involvement of serine 3. Recently, we have also shown that UAG mobilizes endothelial progenitor cells (EPCs), protects them from oxidative stress and senescence and increases de-novo vessel formation. Herein we show that the fragment UAG(6-13) similarly protects EPCs from oxidative stress, further supporting the view that this peptide exhibits the same pharmacological profile and therapeutic potential as its parent molecule.

Unacylated ghrelin fragment promotes survival of pancreatic beta−cells and human pancreatic islets and improves diabetes in streptozotocin−treated neonatal rats.

GRANATA, Riccarda;BRIZZI, Maria Felice;SETTANNI, Fabio;TOGLIATTO, Gabriele Maria;BARAGLI, ALESSANDRA;GHIGO, Ezio
2010-01-01

Abstract

The 28-aminoacid peptide unacylated ghrelin (UAG), although unable to bind the acylated ghrelin (AG) receptor GHS-R1a, exerts many biological effects. UAG, similarly to AG, protects in vitro β-cells and human pancreatic islets against apoptosis, stimulates their proliferation and enhances glucose-induced insulin secretion at physiological concentrations. In vivo, UAG prevents diabetes at adult age in streptozotocin (STZ)-treated neonatal rats by reducing blood glucose, and increasing β-cell mass and insulin secretion. Based on these evidence, we investigated the potential survival effects of UAG fragments in HIT-T15 β-cells and human pancreatic islet cells. These fragments either included or excluded serine-3, the site for ghrelin octanoylation essential for GHS-R1a binding. UAG fragment comprising aminoacids 6-13 displayed survival and antiapoptotic actions equal to or even greater than full length UAG (1-28). Moreover, although to a lesser extent, fragments 1-14 and 1-18 retained all the effects of UAG 1-28, including stimulation of glucose-induced insulin secretion. Conversely, fragments 8-13, 8-12 and, particularly, 1-5 and 17-28, showed reduced or no activity. Notably, UAG(6-13), which showed the best protective effects in vitro, also prevented diabetes at adult age in STZ-treated neonatal rats, by decreasing blood glucose and increasing blood and pancreatic insulin levels, similarly to UAG. These findings indicate that UAG fragments, similarly to the full length peptide, exert protective effects in β-cells and human islets. The strong UAG(6-13)-induced survival action suggests that this fragment may be sufficient per se to display the protective effects of UAG, without involvement of serine 3. Recently, we have also shown that UAG mobilizes endothelial progenitor cells (EPCs), protects them from oxidative stress and senescence and increases de-novo vessel formation. Herein we show that the fragment UAG(6-13) similarly protects EPCs from oxidative stress, further supporting the view that this peptide exhibits the same pharmacological profile and therapeutic potential as its parent molecule.
2010
American Diabetes Association 70th Scientific Sessions
Orlando, Florida
June, 25-29, 2010
Abstract Book
American Diabetes Association:National Service Center, 1701 North Beaureguard Street:Alexandria, VA 22311:(800)232-3472, (703)549-1500, INTERNET: http://www.diabetes.org/diabetscare, Fax: (703)549-6995
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http://professional.diabetes.org/Congress_Display.aspx?TYP=9&CID=71390
Ghrelin fragments; Diabetes
Riccarda Granata; Maria Felice Brizzi; Fabio Settanni; Gabriele Togliatto; Alessandra Baragli; Thierry Abribat; Aart-Jan van Der Lely; Ezio Ghigo...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/93315
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