Molecular pathways associated with oxidative stress in diabetes mellitus.

The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic pathways such as glycolytic, hexosamine, protein kinase C, polyol and advanced glycation end-product (AGE) pathways have been identified as pro-oxidative processes and are usually up-regulated in the diabetics. Inhibition of glyceraldehyde-3-P dehydrogenase by poly-ADP-ribose polymerase 1 and subsequent accumulation of the enzyme substrate (glyceraldehyde-3-P) appears to be central to diabetes-associated oxidative stress. Increased level of glyceraldehyde-3-P activates two major pro-oxidative pathways in diabetes: (i) It activates the AGE pathway, precisely the synthesis of methylglyoxal from non-enzymatic dephosphorylation of the triose phosphates (ii) It activates protein kinase C (PKC) pathway by promoting the synthesis of diacylglycerol. In addition, it causes the accumulation of glycolytic metabolites upstream, and this leads to excessive stimulation of other pro-oxidative pathways such as hexosamine and polyol pathways. This review tends to highlight the main oxidative processes associated with diabetes mellitus.