Glucolipotoxic conditions induce beta-cell iron import, cytosolic ROS formation and apoptosis
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Glucolipotoxic conditions induce beta-cell iron import, cytosolic ROS formation and apoptosis. / Hansen, Jakob Bondo; Dos Santos, Laila Romagueira Bichara; Liu, Ying; Prentice, Kacey J.; Teudt, Frederik; Tonnesen, Morten; Jonas, Jean-Christophe; Wheeler, Michael B.; Mandrup-Poulsen, Thomas.
In: Journal of Molecular Endocrinology, Vol. 61, No. 2, 2018, p. 69-77.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Glucolipotoxic conditions induce beta-cell iron import, cytosolic ROS formation and apoptosis
AU - Hansen, Jakob Bondo
AU - Dos Santos, Laila Romagueira Bichara
AU - Liu, Ying
AU - Prentice, Kacey J.
AU - Teudt, Frederik
AU - Tonnesen, Morten
AU - Jonas, Jean-Christophe
AU - Wheeler, Michael B.
AU - Mandrup-Poulsen, Thomas
PY - 2018
Y1 - 2018
N2 - Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity (GLT) has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species (ROS). Here, we examined if modeling glucolipotoxic conditions by high glucose-high free fatty acid (FFA) exposure (GLT) regulates beta-cell iron transport, by increasing the cytosolic labile iron pool (LIP). In isolated mouse islets, the GLT-induced increase in the LIP catalyzed cytosolic ROS formation and induced apoptosis. We show that GLT-induced ROS production is regulated by an increased 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 (MMP) 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 MMP and beta-cell apoptosis.
AB - Type 2 diabetes (T2D) arises when the pancreatic beta-cell fails to compensate for increased insulin needs due to insulin resistance. Glucolipotoxicity (GLT) has been proposed to induce beta-cell dysfunction in T2D by formation of reactive oxygen species (ROS). Here, we examined if modeling glucolipotoxic conditions by high glucose-high free fatty acid (FFA) exposure (GLT) regulates beta-cell iron transport, by increasing the cytosolic labile iron pool (LIP). In isolated mouse islets, the GLT-induced increase in the LIP catalyzed cytosolic ROS formation and induced apoptosis. We show that GLT-induced ROS production is regulated by an increased 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 (MMP) 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 MMP and beta-cell apoptosis.
KW - intrinsic death pathway
KW - diabetes
KW - insulin secretion
KW - glucolipotoxicity
U2 - 10.1530/JME-17-0262
DO - 10.1530/JME-17-0262
M3 - Journal article
C2 - 30030388
VL - 61
SP - 69
EP - 77
JO - Journal of Molecular Endocrinology
JF - Journal of Molecular Endocrinology
SN - 0952-5041
IS - 2
ER -
ID: 212949575