Type 2 diabetes (T2D) is characterized by impaired beta cell function. The generation of various types of cellular stresses, including oxidative stress and ER stress, and the induction of cellular senescence can contribute to beta cell dysfunction. Recent studies have demonstrated associations between petrochemical exposure and beta cell dysfunction, particularly through induction of cellular stress. One class of compounds, commonly found in crude oil, are sulphur-containing heterocyclic aromatic compounds (S-HACs). S-HACs have been previously demonstrated to induce cellular stress in mammalian cells. This thesis aims to determine if S-HACs can induce cellular stress in beta cells and, consequently, impair beta cell function, particularly insulin production.
Rat pancreatic beta cells, INS-1Es, were treated with two commonly occurring S-HACs, BNT(2,3D) and DBT, at doses which reflect non-occupational exposure levels. Upon treatment, various functional assays and qPCR experiments were performed for examining glucose uptake, ROS production, cellular senescence, ER stress and intracellular insulin production. It was observed that both BNT(2,3D) and DBT significantly increased glucose uptake and ROS production in the beta cells and upregulated the mRNA expression of various ER stress markers. In addition, BNT(2,3D) also induced cellular senescence, likely through a p53-independent pathway. This suggests that S-HACs may induce oxidative stress and ER stress in exposed beta cells, and some S-HACs may cause irreversible cell cycle arrest in response to these cellular stresses. However, intracellular insulin content in the INS-1Es was not altered by exposure to either S-HAC, suggesting that S-HACs may not impair insulin production. Nevertheless, the significant accumulation of ROS in S-HAC-exposed beta cells and the subsequent induction of cellular senescence by some S-HACs may alter other important beta cell functions, including mitochondrial function and insulin secretion, which could lead to the development of T2D; suggesting the potential for S-HACs to be novel beta cell toxicants. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25705 |
| Date | January 2020 |
| Creators | Perera, Ineli |
| Contributors | Holloway, Alison, Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Report, Thesis |
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