The role of the mTOR-Raptor complex in driving hyperuricemia-induced diabetes mellitus
dc.contributor.advisor | Bahn, Andrew | |
dc.contributor.author | Brocherie, Paris Rhiannon | |
dc.date.available | 2018-11-20T00:22:29Z | |
dc.date.copyright | 2018 | |
dc.identifier.citation | Brocherie, P. R. (2018). The role of the mTOR-Raptor complex in driving hyperuricemia-induced diabetes mellitus (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/8608 | en |
dc.identifier.uri | http://hdl.handle.net/10523/8608 | |
dc.description.abstract | Elevated serum uric acid (hyperuricemia) when left untreated can lead to a range of pathologies including gout, cancer and type 2 diabetes mellitus (T2DM). It has been shown that after three days of exposure to hyperuricemic conditions, the viability of pancreatic β-cells decreases. Loss of pancreatic β-cell viability results in reduced insulin secretion, a hallmark in the development of T2DM. The primary aim of this project was to identify what drives the loss of pancreatic β-cell viability under hyperuricemic conditions to identify potential therapeutic targets for the treatment of T2DM. We investigated the effects of hyperuricemia on the mechanistic target of rapamycin (mTOR) complex, of which mTOR complex 1 (mTORC1) regulates cellular autophagy, proliferation and cell viability. A major regulator of mTORC1 is AMP-activated kinase (AMPK) phosphorylating the mTORC1-specific subunit Raptor, and inhibiting mTORC1. Hyperuricemia has been shown to increase AMPK phosphorylation (pAMPK) and consequently AMPK activity. This lead to my hypothesis that hyperuricemia induces loss of cell viability by increasing the phosphorylation of Raptor resulting in reduced mTORC1 activity, thereby causing a reduction in β-cell proliferation and an increase in autophagy driving β-cell apoptosis. To inform the aims of this project, human (1.1B4) and mouse (MIN6) pancreatic β-cell cell lines were utilized. I examined how Raptor and AMPK protein expression and phosphorylation are altered under hyperuricemic conditions using western blot analyses, while proliferation, apoptosis and autophagy assays were employed to determine changes in cell growth and cell death under hyperuricemic conditions. Here we report that both 1.1B4 and MIN6 cells exposed to hyperuricemic conditions have significantly increased activity of AMPK (p < 0.05) despite a significant reduction in AMPK expression (p < 0.005). Further, these cells display a significant reduction in phosphorylation of Raptor (p < 0.0001) despite significant increases in Raptor expression upon exposure to hyperuricemic conditions (p < 0.05). Although Raptor phosphorylation was reduced, mTOR activity appears to be reduced in 1.1B4 cells exposed to hyperuricemic conditions evidenced by the significant increase in autophagy (p < 0.05) and significantly reduced cellular proliferation (p < 0.05). Exposure of 1.1B4 cells to hyperuricemic conditions has no significant effect on cellular apoptosis (p = 0.112). This novel study has identified that hyperuricemia results in reduced mTORC1 activity leading to significantly increased cellular autophagy and reduced proliferation. I have identified that the loss in pancreatic β-cell viability is potentially attributed to reduced mTORC1 activity resulting in increased autophagic cell death. With the established association between hyperuricemia and the development of T2DM, targeting mTORC1 activation may provide a potential therapy for controlling the progression of hyperuricemia to the development of T2DM by maintaining pancreatic β-cell viability. | |
dc.language.iso | en | |
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.subject | Hyperuricemia | |
dc.subject | diabetes mellitus | |
dc.subject | mTOR | |
dc.subject | Raptor | |
dc.subject | diabetes | |
dc.title | The role of the mTOR-Raptor complex in driving hyperuricemia-induced diabetes mellitus | |
dc.type | Thesis | |
dc.date.updated | 2018-11-19T23:09:23Z | |
dc.language.rfc3066 | en | |
thesis.degree.discipline | The Department of Physiology | |
thesis.degree.name | Bachelor of Biomedical Sciences with Honours | |
thesis.degree.grantor | University of Otago | |
thesis.degree.level | Honours | |
otago.interloan | no | |
otago.openaccess | Abstract Only |
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Physiology [155]
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Thesis - Honours [340]