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Title: Role of C-peptide in the vasculature
Author: Al-Isawi, Zahraa J. K.
ISNI:       0000 0004 7964 0843
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Subjects with diabetes are at high risk of developing long-term complications, including cardiovascular diseases. Recent data suggest that diabetes maybe a dual hormone deficiency disease in which secretion of both insulin and C-peptide is insufficient. Insulin is supplemented as part of treatment regimes, while altered C-peptide levels remain untreated. Herein, the potential beneficial effect of C-peptide replacement on vascular system health was investigated. Using cultured human endothelial cells (EAhy926), incubation with 5nM C-peptide resulted in an upregulation of protein expression of endothelial nitric oxide synthase, suggesting a direct regulatory effect for C-peptide on normal endothelial cell function. This was associated with stimulatory effects of key intracellular signalling pathway MAP kinase (ERK1/2). This ERK1/2 activation in EA.hy926 cells was not associated with cell growth or increased protein content. In apoptotic endothelial cells, C-peptide exerted a moderate stimulatory effect on microparticle generation as a measure of endothelial cell function. This effect was restored close to normal level by treating the cells with pertussis toxin suggesting that C-peptide acted through a G-protein coupled receptor. C-peptide-derived miroparticles analysed by flow cytometry demonstrated CD31 and CD105 expression as well as superficial phosphatidylserine. Further confirmation of the vesicle morphology and size range was performed using electron microscopy and nanoparticle tracking analysis. Preliminary investigation of potential biological significance of these MPs did not reveal obvious effects on endothelial apoptosis level as assessed by Caspase-3 cleavage, or their inflammatory status as evaluated by the expression of intercellular adhesion molecule 1 and E-selectin adhesion molecules, and Interleukin-8 secretion. However, proteomic analysis of C-peptide-mediated MPs highlighted the possibility of selective packaging of biomolecules within these vesicles. The proposed protective effect of C-peptide on the vascular system was also investigated in vivo. Administration of C-peptide subcutaneously in type 1 diabetic rats attenuated von willebrand factor overexpression in aortic intima of these animals. Furthermore, C-peptide treatment retarded collagen deposition in the vascular wall suggesting an important role for C-peptide in extracellular matrix remodelling. Therefore, in contrast to the older views that portrayed C-peptide as an inert molecule with no bioactivity, the data presented in this study support an active role for C-peptide in the vasculature.
Supervisor: Brunskill, Nigel ; Bevington, Alan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available