Glucose-induced cellular dysfunction: The role of protein kinase C.

2015-11-19T08:51:38Z (GMT) by Bryan Williams
This thesis is divided into four sections. The first section contains the introductory overview in which I review the previous hypotheses that have implicated high extracellular glucose concentrations in the pathogenesis of cellular dysfunction and injury. These previous studies set the stage for the presentation of my work in which I have explored the novel hypothesis that glucose-induced protein kinase C activation may provide a final common path for many aspects of cellular dysfunction in diabetes mellitus. The second section contains my published works which reported the first detailed characterisation of glucose-induced protein kinase C activity and subsequently explored the potential biological significance of this ubiquitous intracellular signalling pathway with regard to a variety of pathophysiological changes in cell function. The third section of this thesis also contains my published works which illustrate how my studies have subsequently developed with specific reference to our description of the potentially important role of a recently discovered vascular permeability factor in the development of vascular dysfunction in diabetes mellitus. This section culminates in the presentation of my latest study which has just been submitted for publication to the Journal of Clinical Investigation. This study demonstrates that high extracellular glucose concentrations directly stimulate vascular permeability gene expression and peptide production by human vascular smooth muscles via a protein kinase C-dependent mechanism. In so doing, this latest study illustrates the consistency of the theme that began and continues throughout this thesis; notably, the role of protein kinase C in mediating many diverse aspects of glucose-induced cellular dysfunction. Finally, in section four, I conclude the thesis by reviewing the main features of the published works contained within it and I describe how future work could extend these observations and provide the basis for possible new therapeutic interventions designed to attenuate glucose-induced cellular injury.




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