Increased Oxidative Load in Diabetes the Role of Hyperglycemia

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Many but not all studies have found increased accumulation of oxidation byproducts in diabetes. Lipid peroxidation byproducts such as exhaled ethane or pentane, malondialdehyde, conjugated dienes and F2-isoprostanes are increased in diabetic subjects and in animal models of diabetes [for review see 3, 4]. Similarly, oxidation byproducts of proteins and deoxynucleic acids (DNA) are increased.

The mechanisms underlying the increased oxidative byproducts in diabetes are multiple. These mechanisms can be generally classified as either a consequence of a glucose-induced increase in the production of reactive oxygen species (ROS), decreased antioxidant defense capacity, or the inability to eliminate the oxidized byproducts efficiently. The latter is not supported by as much experimental evidence as the former two mechanisms.

Through glycolysis, glucose is converted to pyruvate that enters the tricar-boxylic acid cycle, increasing the electron transport chain and, in the process, ROS is produced. This process has been shown to occur in several studies of endothelial as well as other cell cultures. Glucose-induced ROS production can be ameliorated with both conventional, such as vitamin C and E [5], and unconventional antioxidants, such as statins [6] and carvedelol [7]. It is noteworthy that in these experimental conditions the rate of ROS production decreases after the second or third hour of treatment suggesting that adaptive mechanisms are activated to ameliorate the initial surge of oxidative activity. These adaptations may originate at nuclear and extranuclear sites of action. Several genes are now identified that have antioxidant response elements (AREs) in the promoter region. The antioxidant response gene family involves at least six genes on at least two different chromosomes. Examples include nicotinamide adenine dinucleotide phosphate (NADPH) quinone oxi-doreductase I and II (hNQO1 and hNQO2) genes that can mount a coordinated response to oxidant stress [8]. Other AREs have been identified and been shown to respond to conventional antioxidants sometimes downregulat-ing gene products that have cardioprotective properties [9]. Thus the genomic response to oxidants and antioxidants could have both protective and deleterious consequences.

In addition to being a substrate for cellular respiration, glucose can induce ROS generation through multiple pathways including the promotion of glycation of proteins and activation of protein kinase C (PKC) activity [2]. Furthermore, glucose has auto-oxidative potential that has been demonstrated in cell-free systems [10]. In comparison to other simple sugars, fructose has the most potent auto-oxidative potential while deoxyribose has the least capacity of auto-oxidation [10].

Chronic hyperglycemia can also promote oxidative stress through interference with antioxidant defense systems. Diabetic individuals, especially those who are poorly controlled, are likely to develop multiple micronutrient deficiencies some of which have antioxidant activities [3, 11]. Of all the potential antioxidant deficiencies, depletion of the intracellular content of ascorbate can occur because of direct inhibition of the cellular uptake of dehydroascor-bate by glucose [12]. Nevertheless, the effect of uncontrolled hyperglycemia on antioxidant defense capacity extends beyond individually known micronu-trients [13]. The precise metabolic pathway by which hyperglycemia reduces the antioxidative defense capacity is not completely clear, but appears to be at least partly secondary to overconsumption of antioxidants in the presence of increased production of ROS.

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