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Se‐glutathione peroxidase mimic ebselen serves as a novel regulator of insulin secretion in mouse islets
Author(s) -
Wang Xinhui,
Lei Xin Gen
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.860.11
Subject(s) - ebselen , gpx1 , sod1 , glutathione peroxidase , medicine , chemistry , endocrinology , superoxide dismutase , pancreatic islets , regulator , insulin , pharmacology , islet , biology , biochemistry , enzyme , gene
Our laboratory has previously shown impaired glucose‐stimulated insulin secretion (GSIS) in mice deficient in Se‐glutathione peroxidase 1 (GPX1 −/− , Cu,Zn‐superoxide dismutase (SOD1 −/− ), or both enzymes (DKO). This study was to determine if and how the GPX1 (ebselen) and SOD1 (copper diisopropylsalicylate, CuDIPs) mimics rescued the impairment. Pancreatic islets were isolated from the three knockout mouse lines (3–6 mo, male) and their wild‐type (WT), treated with ebselen (50 μM), CuDIPs (10 μM), or Se (100 nM, sodium selenite) for 5 h, and incubated for 60 min with 2.8 or 16.7 mM glucose to collect medium supernatants and islets for assays. Ebselen, but not CuDIPS or Se, promoted (P < 0.01) GSIS in islets of all genotypes. Ebselen also rescued GSIS and improved glucose clearance in the GPX1 −/− mice, and the rescue was associated with coordinated responses of four key functional proteins of GSIS. Bioinformatics and Q‐PCR analysis were followed to identify four potential signaling pathways for ebselen to regulate the gene expression of these four factors. A siRNA study verified PGC‐1α in the ARE signaling pathway as the key effector for the global regulation of ebselen on GSIS. In conclusion, we revealed a novel role and signal pathway of ebselen in rescuing GSIS of GPX1 deficient islets and mice, a distinct comparison of GPX1 and SOD1 in regulating GSIS, and a new strategy to treat insulin secretion disorders (NIH DK 53018).