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A Murine Pancreatic Islet Cell-based Screening for Diabetogenic Environmental Chemicals
Published on: June 25, 2018
Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stress
1Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665, Kong Jiang Road, Shanghai, 200092, China.
Aim:
This study evaluated the direct effects of advanced glycation end-products (AGEs) on pancreatic β cells, including cellular viability, generation of reactive oxygen species (ROS) and insulin secretion, and also looked for the main source of ROS in INS-1 cells and the possible molecular mechanism(s) of cell injury by AGEs.
Methods:
INS-1 cells were cultured with 100, 200 and 500 mg/L of AGEs for specific periods of time. Cell apoptosis was determined by ELISA and real-time PCR assays. ROS were detected by DCFH-DA and MitoSOX Red probes with a flow cytometer, NADPH oxidase activity was measured by lucigenin chemiluminescence and MAPK phosphorylation was measured by Western blot tests.
Results:
Both cell apoptosis and ROS generation increased in AGE-treated cells in a dose-dependent way, and both the mitochondrial electron transport chain and NADPH oxidase pathway participated in ROS generation, although the role of the mitochondrial pathway was earlier and more important. AGEs exerted a toxic effect on insulin secretion that could be largely reversed by inhibiting ROS.
Conclusion:
AGEs injured INS-1 cells by oxidative stress mainly through the mitochondrial pathway, although the JNK and p38 MAPK signaling pathways were also key modulators in ROS-mediated β-cell death.
Insights
Advanced glycation end-products (AGEs) cause pancreatic beta cell damage via oxidative stress, primarily through mitochondrial pathways. Inhibiting reactive oxygen species (ROS) can reverse AGEs
Area of Science:
- Endocrinology
- Cell Biology
- Biochemistry
Background:
- Advanced glycation end-products (AGEs) are implicated in diabetic complications.
- Pancreatic beta cells are crucial for insulin production and are vulnerable to oxidative stress.
Purpose of the Study:
- To investigate the direct impact of AGEs on pancreatic beta cell viability, reactive oxygen species (ROS) generation, and insulin secretion.
- To identify the primary source of ROS in INS-1 cells and elucidate the molecular mechanisms of AGE-induced cell injury.
Main Methods:
- INS-1 cells were exposed to varying concentrations of AGEs.
- Cell apoptosis, ROS generation, NADPH oxidase activity, and MAPK phosphorylation were assessed using techniques including ELISA, real-time PCR, flow cytometry, and Western blotting.
Main Results:
- AGEs induced dose-dependent increases in beta cell apoptosis and ROS generation.
- Both mitochondrial and NADPH oxidase pathways contributed to ROS production, with the mitochondrial pathway being more prominent early on.
- AGEs impaired insulin secretion, an effect largely mitigated by ROS inhibition.
Conclusions:
- AGEs inflict damage on INS-1 cells through oxidative stress, predominantly via the mitochondrial pathway.
- JNK and p38 MAPK signaling pathways play significant roles in ROS-mediated beta cell death.
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