The Maillard reaction is considered to play an important role in the microvascular complications of diabetes. This reaction produces irreversible adducts on proteins known as advanced glycation end products or AGEs. Recent studies suggest that dicarbonyl compounds produced during the Maillard reaction and by other metabolic pathways are the major precursors of AGEs in vivo. In this regard, the dicarbonyl compounds methylglyoxal and glyoxal are significant, since their formation appears to be directly linked to degree of glycemia in diabetes. Our recent studies indicate that specific products derived from these two dicarbonyls accumulate at a higher rate in plasma and tissue proteins in diabetes than in normal controls. Our studies also suggest that oxidative stress coupled to hyperglycemia leads to dicarbonyl stress in diabetes and results in enhanced formation of AGEs. Although other investigators report deleterious effects of AGEs on microvascular cells, some of these studies were done with AGEs generated with high concentrations of glucose. We believe that interpretation of such studies may be difficult, since they do not rule out specific effects of dicarbonyl compounds. In this proposal, we will determine the relationship of dicarbonyls with diabetic retinopathy in human and experimental diabetes and then resolve the biochemical and molecular pathways involved in retinal cell damage by dicarbonyls. Our experiments will use highly sensitive immunological and chromatographic methods for quantification of dicarbonyl-AGEs.
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