Hyperuricemia driven pancreatic β-cell dysfunction through Rictor, a subunit of mTORC2
|dc.contributor.author||Nolan, Devon James|
|dc.identifier.citation||Nolan, D. J. (2018). Hyperuricemia driven pancreatic β-cell dysfunction through Rictor, a subunit of mTORC2 (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/8572||en|
|dc.description.abstract||The prevalence of diabetes mellitus, specifically type two diabetes mellitus (T2DM), is rapidly rising worldwide prompting research into mechanisms involved in T2DM progression and development. High plasma concentration of the purine metabolite, uric acid, is defined as hyperuricemia and has been linked to the development of multiple pathologies, including T2DM. Exposing the insulin-producing pancreatic β-cells to hyperuricemic conditions induces β-cell dysfunction characterized by loss of proliferation and increased apoptosis. However, the mechanism behind this hyperuricemia-induced β-cell dysfunction is still a mystery. A proposed mechanism involves hyperuricemia-induced dysfunction of the cell viability regulator, the mechanistic target of rapamycin (mTOR). mTOR is a serine-threonine kinase which functions in two distinct complexes, mTORC1 and mTORC2. mTORC2 is a pivotal regulator of proliferative and apoptotic signaling within the β-cell and reduction in mTORC2 signaling has been postulated to be involved in the development of diabetes. Rictor is an integral mTORC2 subunit which stabilizes the complex to enable mTORC2 signaling. In addition, Rictor has been identified to be modulated under pathological conditions. Therefore, the aim of this research was to identify if Rictor is modulated under hyperuricemic conditions. To address this aim, Rictor’s total expression and inhibitory Thr1135 phosphorylation were assessed in mouse (MIN6) and human (1.1B4) pancreatic β-cell lines treated with normouricemic (300 µmol/l) and hyperuricemic (750 µmol/l) uric acid conditions. In addition, the proliferation and apoptosis within both cell lines were assessed under normouricemic and hyperuricemic conditions. The current study demonstrated that hyperuricemia did not alter total Rictor expression or phosphorylation within MIN6 or 1.1B4 cells, however, the proportion of the total Rictor that was phosphorylated was significantly reduced in MIN6 (p=0.0457), and trends towards a reduction in 1.1B4 cells (p=0.0796). Furthermore, hyperuricemia significantly decreased the proliferation (p=0.0419), but produced no significant change to the rate of apoptosis within 1.1B4 cells (p=0.1133). This year’s research is the first to document a hyperuricemia-dependent modulation of Rictor within pancreatic β-cell lines and a hyperuricemia-induced reduction in proliferation of 1.1B4 cells. The results suggest a disruption in Rictor’s association with mTOR, thereby, suppressing mTORC2 signaling and reducing β-cell proliferation, leading to β-cell dysfunction, therefore, linking Rictor and mTORC2 activity with hyperuricemia-induced development of diabetes.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Hyperuricemia driven pancreatic β-cell dysfunction through Rictor, a subunit of mTORC2|
|thesis.degree.name||Bachelor of Biomedical Sciences with Honours|
|thesis.degree.grantor||University of Otago|
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