Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets

Antioxid Redox Signal. 2014 Jan 10;20(2):191-203. doi: 10.1089/ars.2013.5361. Epub 2013 Aug 9.

Abstract

Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice.

Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1α pathway.

Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H2O2) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H2O2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1α as the main mediator for that link.

Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Regina Brigelius-Flohe, Vadim Gladyshev, Dexing Hou, and Holger Steinbrenner.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Azoles / pharmacology*
  • Glucokinase / metabolism
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Glucose Transporter Type 2 / metabolism
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism*
  • Glutathione Reductase / metabolism
  • Homeodomain Proteins / metabolism
  • Hydro-Lyases / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Ion Channels / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism
  • Molecular Mimicry
  • Organoselenium Compounds / pharmacology*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species / metabolism
  • Selenium / pharmacology
  • Signal Transduction / drug effects
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Uncoupling Protein 2

Substances

  • Azoles
  • Glucose Transporter Type 2
  • Homeodomain Proteins
  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • Organoselenium Compounds
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Trans-Activators
  • Transcription Factors
  • Uncoupling Protein 2
  • pancreatic and duodenal homeobox 1 protein
  • ebselen
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Glutathione Reductase
  • Glucokinase
  • Hydro-Lyases
  • lactate dehydratase
  • Selenium
  • Glucose