Glucolipotoxic conditions induce beta-cell iron import, cytosolic ROS formation and apoptosis

Hansen, Jakob B;Dos Santos, Laila RB;Liu, Ying;Prentice, Kacey J;Mandrup-Poulsen, Thomas;et.al.
(2018) Journal of Molecular Endocrinology — Vol. 61, p. 69-77 (2018)

Files

Hansenetal2018_Acceptedversion.pdf
  • Open Access
  • Adobe PDF
  • 1.12 MB
Download

Details

Authors
  • Hansen, Jakob BUniversity of Copenhagen, Dept. of Biomedical Sciences
    Author
  • Dos Santos, Laila RBUCLouvain
    Author
  • Liu, YingUniversity of Toronto, Dept. of Physiology
    Author
  • Prentice, Kacey JUniversity of Toronto, Dept. of Physiology
    Author
  • Jonas, Jean-Christopheorcid-logoUCLouvain
    Author
  • Mandrup-Poulsen, ThomasUniversity of Copenhagen, Dept. of Biomedical Sciences
    Author
Show more
Abstract
Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species (ROS). Here we examined if modelling glucolipotoxic conditions by high glucose-high free fatty acid (FFA) exposure (GLT) regulate beta-cell iron transport, thereby increasing the cytosolic labile iron pool and iron-catalyzed ROS formation. We show that GLT -induced ROS production is regulated by an increased labile iron pool (LIP) associated with elevated expression of genes regulating iron import. Using pharmacological and transgenic approaches, we show that iron reduction and decreased iron import protects from GLT-induced ROS production, prevents impairment of the mitochondrial membrane potential, and inhibits apoptosis. This study identifies a novel pathway underlying GLT-induced apoptosis involving increased iron import, generation of hydroxyl radicals from hydrogen peroxide through the Fenton reaction in the cytosolic compartment associated with dissipation of the mitochondrial membrane potential and beta cell apoptosis.
Affiliations

Citations

  • APA
  • Chicago
  • FWB

Hansen, J. B., Dos Santos, L. R., Liu, Y., Prentice, K. J., Teudt, F., Tonnesen, M., Jonas, J.-C., Wheeler, M. B., & Mandrup-Poulsen, T. (2018). Glucolipotoxic conditions induce beta-cell iron import, cytosolic ROS formation and apoptosis. Journal of Molecular Endocrinology, 61, 69-77. https://doi.org/10.1530/JME-17-0262 (Original work published 2018)