Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599719
Title: The association of PAI-1 with diabetes mellitus : could insulin receptor processing be a link?
Author: Griffiths, S. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Abstract:
Inflammation is associated with the Metabolic Syndrome, and PAI-1 is a marker of inflammation, so it is feasible that regulation of PAI-1 in inflammatory cells could be important. I find that TGFβ is a potent stimulator. In contrast, though, to most studies in other cell types, insulin inhibits TGFβ-stimulated PAI-1 production. Nevertheless, leukocytes produce such low levels of PAI-1 compared to adipocytes that they are unlikely to contribute significantly to circulating PAI-1 levels, although it is plausible that leukocyte-derived PAI-1 may have important local effects during inflammation. To study PAI-1 regulation in humans, I measured PAI-1 in samples from a clinical study and analysed the relationship with TGFβ and Metabolic Syndrome risk factors. PAI-1 inhibits plasminogen activators and thrombin, all serine proteases, by forming an SDS stable complex. Inhibition of plasminogen activators is known to cause both hypercoagulability ain increased collagen deposition. PAI-1 has also been proposed to inhibit thrombin in certain circumstances. Here, I show that PAI-1 also forms an SDS stable complex with furin. Furin is another of the serine proteases and belongs to the proprotein convertase family. The furin reaction with PAI-1 occurs on a similar timescale to the thrombin reaction and may be as physiologically relevant. Substrates of furin include the insulin receptor, TGFβ and LRP (LDL receptor-related protein). Inhibition of furin, thereby reducing the processing of these substrates, may therefore lead to insulin resistance, atherosclerosis and dyslipidaemia. For this project we decided to focus on insulin receptor processing as a marker of proprotein convertase activity in vivo. A very subtle effect of processing could, over time, have a dramatic effect on insulin sensitivity. An ELISA system was developed to measure the amount of mature insulin receptor and proreceptor. Unfortunately, it did not detect insulin receptor in human clinical samples, but was used to measure the effect of furin inhibition and PAI-1 on insulin receptor processing in cultured cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.599719  DOI: Not available
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