Abstract
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
Original language | English |
---|---|
Journal | Free Radical Biology and Medicine |
Volume | 177 |
Issue number | Suppl. 1 |
Pages (from-to) | S37-S38 |
ISSN | 0891-5849 |
DOIs | |
Publication status | Published - 2021 |
Event | Annual Meeting of the Society-for-Free-Radical-Research-Europe (SFRR-E) - Redox Biology in the 21st Century - A New Scientific Discipline - Belgrade, Serbia Duration: 15 Jun 2021 → 18 Jun 2021 |
Conference
Conference | Annual Meeting of the Society-for-Free-Radical-Research-Europe (SFRR-E) - Redox Biology in the 21st Century - A New Scientific Discipline |
---|---|
Country/Territory | Serbia |
City | Belgrade |
Period | 15/06/2021 → 18/06/2021 |