The role of RNA oxidation in islet dysfunction in Type 2 diabetes
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The role of RNA oxidation in islet dysfunction in Type 2 diabetes. / Sileikaite, Inga; Davies, Michael J.; Mandrup-Poulsen, Thomas; Hawkins, Clare L.
In: Free Radical Biology and Medicine, Vol. 177, No. Suppl. 1 , 2021, p. S37-S38.Research output: Contribution to journal › Conference abstract in journal › Research
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TY - ABST
T1 - The role of RNA oxidation in islet dysfunction in Type 2 diabetes
AU - Sileikaite, Inga
AU - Davies, Michael J.
AU - Mandrup-Poulsen, Thomas
AU - Hawkins, Clare L.
PY - 2021
Y1 - 2021
N2 - Oxidative stress and reactive oxygen species (ROS) play a key role in the development of insulin resistance, β-cell dysfunction, and impaired glucose tolerance in type 2 diabetes (T2D). ROS initiate reactions that promote the modification of biological molecules and aberrant signalling to result in cellular dysfunction and death. RNA could be a key target for ROS due to its localization within the cells and lack of RNA repair mechanisms. The nucleobase guanosine, is highly sensitive to oxidation, which forms 8-oxoguanosine (8-oxoGuo), a product strongly associated with T2D morbidity. However, the pathway by which 8-oxoGuo is formed in patients with T2D and whether 8-oxoGuo has a causal role in disease progression and islet dysfunction remains unknown. In this study, we examined the reactivity of 8-oxoGuo and related modified nucleoside with INS-1 cells, as β-cell model, and assessed the pathways responsible for ROS formation on exposure of β-cells to pro-inflammatory cytokines or glucolipotoxicity (GLT). Initial studies focused on the effect of the treatments on intracellular thiol concentration and the formation of hydrogen peroxide (H2O2). Exposure of INS-1 cells to TNFα, IL-1β or GLT conditions (25 mM glucose / 100 mM palmitic acid) resulted in a significant time-dependent loss in thiols. Exposure to TNFα and/or IL-1β, but not GLT, resulted in an increase in H2O2 formation. Experiments were also performed with INS-1E cells treated with 8-oxoGuo, 8-oxodeoxyguanosine (8-oxodG), 8-oxoGTP, 8-chloroguanosine (8ClG), and 8-chlorodeoxyguanosine (8CldG). This resulted in a non-significant loss in thiols, but an elevation in the production of H2O2, particularly with 8ClG after 4 and 24 h exposure times. In both sets of experiments, evidence was obtained for the alteration of 8-oxoGuo and 8-oxodG within the cellular RNA and DNA respectively. Overall, this project provides new data regarding oxidative pathways in different T2D models of β-cell dysfunction
AB - Oxidative stress and reactive oxygen species (ROS) play a key role in the development of insulin resistance, β-cell dysfunction, and impaired glucose tolerance in type 2 diabetes (T2D). ROS initiate reactions that promote the modification of biological molecules and aberrant signalling to result in cellular dysfunction and death. RNA could be a key target for ROS due to its localization within the cells and lack of RNA repair mechanisms. The nucleobase guanosine, is highly sensitive to oxidation, which forms 8-oxoguanosine (8-oxoGuo), a product strongly associated with T2D morbidity. However, the pathway by which 8-oxoGuo is formed in patients with T2D and whether 8-oxoGuo has a causal role in disease progression and islet dysfunction remains unknown. In this study, we examined the reactivity of 8-oxoGuo and related modified nucleoside with INS-1 cells, as β-cell model, and assessed the pathways responsible for ROS formation on exposure of β-cells to pro-inflammatory cytokines or glucolipotoxicity (GLT). Initial studies focused on the effect of the treatments on intracellular thiol concentration and the formation of hydrogen peroxide (H2O2). Exposure of INS-1 cells to TNFα, IL-1β or GLT conditions (25 mM glucose / 100 mM palmitic acid) resulted in a significant time-dependent loss in thiols. Exposure to TNFα and/or IL-1β, but not GLT, resulted in an increase in H2O2 formation. Experiments were also performed with INS-1E cells treated with 8-oxoGuo, 8-oxodeoxyguanosine (8-oxodG), 8-oxoGTP, 8-chloroguanosine (8ClG), and 8-chlorodeoxyguanosine (8CldG). This resulted in a non-significant loss in thiols, but an elevation in the production of H2O2, particularly with 8ClG after 4 and 24 h exposure times. In both sets of experiments, evidence was obtained for the alteration of 8-oxoGuo and 8-oxodG within the cellular RNA and DNA respectively. Overall, this project provides new data regarding oxidative pathways in different T2D models of β-cell dysfunction
U2 - 10.1016/j.freeradbiomed.2021.08.116
DO - 10.1016/j.freeradbiomed.2021.08.116
M3 - Conference abstract in journal
VL - 177
SP - S37-S38
JO - Free Radical Biology & Medicine
JF - Free Radical Biology & Medicine
SN - 0891-5849
IS - Suppl. 1
T2 - Annual Meeting of the Society-for-Free-Radical-Research-Europe (SFRR-E) - Redox Biology in the 21st Century - A New Scientific Discipline
Y2 - 15 June 2021 through 18 June 2021
ER -
ID: 319405996