IA-2β, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion

摘要

Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a β-cell autoantigen for type 1 diabetes, IA-2β. Administration of ghrelin increased IA-2β mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and βTC3). However, the expression of IA-2, another structurally related β-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2β, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2β expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2β induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2β, and glucose-stimulated insulin secretion.