Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Khajag Koulajian, Alexander Ivovic, Kaitai Ye, Tejas Desai, Anu Shah, I. George Fantus, Qitao Ran, Adria Giacca

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced β-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced β-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and β-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired β-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased β-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of β-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced β-cell dysfunction.

Original languageEnglish (US)
Pages (from-to)E254-E262
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number2
DOIs
StatePublished - Jul 15 2013

Keywords

  • Glutathione peroxidase 4
  • In vivo
  • Lipid peroxide
  • Lipotoxicity
  • Oxidative stress
  • β-cell dysfunction

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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