Obestatin and ghrelin inhibit apoptosis of human pancreatic islet endothelial cells in high glucose culture
Enrica Favaro, Maria Maddalena Zanone, Ilaria Miceli, Fabio Settanni, Giovanni Camussi, Paolo Cavallo Perin, Ezio Ghigo & Riccarda Granata
Pancreatic islet microendothelium exhibits unique structural and functional features, in an interdependent physical and functional relationship with the neighbouring β-cells. Glucose toxicity is not solely restricted to β-cells, but affects also survival, proliferation of human pancreatic islet endothelial cells, thus possibly contributing to β-cell function impairment and β-cell loss. It has been previously demonstrated that the ghrelin gene derived peptides, namely acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (Ob), prevent apoptosis of pancreatic β-cells and human pancreatic islets. Therefore, based on our previous findings, we analyzed the effects of hyperglycemia on human pancreatic islet microendothelial cells (MECs), the underlying signaling pathways, and whether AG, UAG and would reverse the response of islet MECs to high glucose conditions. Under high glucose treatment, proliferation of MECs progressively decreased and apoptosis increased, accompanied by a reduced activation of the survival signaling pathway PI3K/Akt. Incubation with AG, UAG or Ob (10 nM) inhibited apoptosis and increased Akt phosphorylation. The antiapoptotic effect of the peptides was blocked by inhibition of adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) and PI3k/Akt signaling pathways. These results suggest that the ghrelin gene-derived peptides promote islet microendothelium survival. Moreover, their survival effect involves the PI3K/Akt signaling pathway. These peptides could therefore represent a potential tool to improve islet vascularization and, indirectly, islet function.