Obestatin Promotes Survival of Pancreatic β-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of β-Cell Mass and Function

摘要: OBJECTIVE— Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of β-cells and human pancreatic islets underlying signaling pathways. RESEARCH DESIGN AND METHODS— β-Cells were used to assess cell proliferation, survival, apoptosis, intracellular signaling, expression. RESULTS— showed specific binding HIT-T15 INS-1E β-cells, bound glucagon-like peptide-1 receptor (GLP-1R), recognized sites. exerted proliferative, antiapoptotic effects under serum-deprived conditions interferon-γ/tumor necrosis factor-α/interleukin-1β treatment, particularly at pharmacological concentrations. Ghrelin antagonist [D-Lys 3 ]-growth hormone releasing peptide-6 anti-ghrelin antibody prevented obestatin-induced in islets. islet cells released obestatin, addition anti-obestatin reduced their viability. increased β-cell cAMP activated extracellular signal–related kinase 1/2 (ERK1/2) phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its was blocked inhibition adenylyl cyclase/cAMP/protein A (PKA), PI 3-kinase/Akt, ERK1/2 signaling. Moreover, upregulated GLP-1R mRNA insulin substrate-2 (IRS-2) expression phosphorylation. The exendin-(9-39) survival. In islets, immunoreactivity colocalized with that ghrelin, promoted cytokine-induced apoptosis through increase involvement cyclase/cAMP/PKA 1 ) induced ERK1/2, also response element–binding protein phosphorylation; 2 stimulated secretion expression; GLP-1R, IRS-2, duodenal homeobox-1, glucokinase mRNA. CONCLUSIONS— These results indicate promotes stimulates main regulatory genes, identifying new role for this within endocrine pancreas.