AbstractAdvanced glycated end-products (AGEs) are a heterogenous group of compounds formed through the Maillard reaction. During AGE formation, reactive α-dicarbonyls are formed, such as glyoxal (GO) and methylglyoxal (MG). These α-dicarbonyls are present at elevated concentrations in diabetes, and are frequently implicated in the initiation and progression of diabetic complications. Previous research has linked α-dicarbonyls with formation of reactive oxygen species (ROS) and inflammation. However, much of the prior work has been conducted using concentrations of α-dicarbonyls that are substantially higher than can be generated in vivo, and the biochemistry has been investigated under conditions (e.g. pH) outside the physiological range. The aim of the work presented in this thesis was to test the hypothesis that GO and MG are pro-oxidant and pro-inflammatory at (patho)physiological concentrations in both monocytes and pancreatic β-cells.
In this work several new and important observations have been made regarding the action of α-dicarbonyls on oxidative stress and inflammation. 1) The amount of oxidative species production by α-dicarbonyls in glycation reactions with amino acids and proteins may be so low as to be negligible in vivo, despite previous evidence to the contrary. 2) α-dicarbonyls did not appear to generate oxidative stress within inflammatory cells nor pancreatic β-cells by depleting the levels of GSH. 3) At least in the β-cell model, the mechanism of action of the α-dicarbonyls did not involve dysregulation of the antioxidant SOD enzymes. 4) Neither α-dicarbonyl significantly affected insulin production by β-cells, except at cytotoxic concentrations. 5) Treatment of inflammatory cells with α-dicarbonyls induced release of the proinflammatory cytokine IL-8. 6) In both immune cells and pancreatic β-cells, α-dicarbonyls were involved in O2.- generation by activation and/or upregulation of NADPH oxidase. 7) Despite the structural similarities of α-dicarbonyls, they have distinct mechanisms of action with respect to oxidative stress.
|Date of Award||1 Oct 2010|
|Supervisor||Ian Megson (Supervisor), Sandra MacRury (Supervisor) & Adriano G Rossi (Supervisor)|