Des-acyl ghrelin fragments and analogues promote survival of pancreatic β-cells and human pancreatic islets and prevent diabetes in streptozotocin-treated rats

Riccarda Granata; Fabio Settanni; Michel Julien; Rita Nano; Gabriele Togliatto; Antonella Trombetta; Davide Gallo; Lorenzo Piemonti; Maria Felice Brizzi; Thierry Abribat; Aart-Jan van Der Lely; Ezio Ghigo

doi:10.1021/jm201223m

Des-acyl ghrelin fragments and analogues promote survival of pancreatic β-cells and human pancreatic islets and prevent diabetes in streptozotocin-treated rats

J Med Chem. 2012 Mar 22;55(6):2585-96. doi: 10.1021/jm201223m. Epub 2012 Mar 5.

Authors

Riccarda Granata¹, Fabio Settanni, Michel Julien, Rita Nano, Gabriele Togliatto, Antonella Trombetta, Davide Gallo, Lorenzo Piemonti, Maria Felice Brizzi, Thierry Abribat, Aart-Jan van Der Lely, Ezio Ghigo

Affiliation

¹ Laboratory of Molecular and Cellular Endocrinology, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy. riccarda.granata@unito.it

PMID: 22352743
DOI: 10.1021/jm201223m

Abstract

Des-acyl ghrelin, although devoid of binding to ghrelin receptor (GRLN), exerts many biological effects, including regulation of glucose and lipid metabolism. Indeed, des-acyl ghrelin promotes pancreatic β-cell and human islet cell survival and prevents diabetes in streptozotocin (STZ) treated rats. We investigated whether des-acyl ghrelin fragments excluding serine(3), which is essential for binding to GRLN, would display similar actions. Among the different compounds tested, des-acyl ghrelin((6-13)) and des-acyl ghrelin((6-13)) with alanine substitutions or cyclization, but not with d-amino acid substitutions, showed the best survival effect, similar to des-acyl ghrelin. Des-acyl ghrelin((6-13)) even prevented diabetes in STZ-treated rats and protected human circulating angiogenic cells from oxidative stress and senescence, similar to des-acyl ghrelin. These results suggest that not only full-length des-acyl ghrelin but also short des-acyl ghrelin fragments have clear beneficial effects on several tissues in vitro and in vivo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Cell Line
Cell Survival / drug effects
Cellular Senescence / drug effects
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / pathology
Diabetes Mellitus, Experimental / prevention & control*
Endothelial Cells / cytology
Endothelial Cells / drug effects
Ghrelin / analogs & derivatives*
Ghrelin / chemistry*
Ghrelin / pharmacology
Humans
Insulin-Secreting Cells / cytology
Insulin-Secreting Cells / drug effects*
Islets of Langerhans / cytology
Islets of Langerhans / drug effects*
Models, Molecular
Molecular Sequence Data
Oxidative Stress
Peptide Fragments / chemistry*
Peptide Fragments / pharmacology
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology
Peptidomimetics / chemistry*
Peptidomimetics / pharmacology
Rats
Rats, Sprague-Dawley
Stem Cells / metabolism
Stem Cells / pathology
Stereoisomerism
Streptozocin
Structure-Activity Relationship

Substances

Ghrelin
Peptide Fragments
Peptides, Cyclic
Peptidomimetics
Streptozocin