Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress

Abstract

Chronic overnutrition creates chronic hyperglycemia that can gradually induce insulin resistance and insulin secretion impairment. These disorders, if not intervened, will eventually be followed by appearance of frank diabetes. The mechanisms of this chronic pathogenic process are complex but have been suggested to involve production of reactive oxygen species (ROS) and oxidative stress. In this review, I highlight evidence that reductive stress imposed by overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more ROS production. The elevated levels of both NADH and ROS can inhibit and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH), respectively, resulting in blockage of the glycolytic pathway and accumulation of glycerol 3-phospate and its prior metabolites along the pathway. This accumulation then initiates all those alternative glucose metabolic pathways such as the polyol pathway and the advanced glycation pathways that otherwise are minor and insignificant under euglycemic conditions. Importantly, all these alternative pathways lead to ROS production, thus aggravating cellular oxidative stress. Therefore, reductive stress followed by oxidative stress comprises a major mechanism of hyperglycemia-induced metabolic syndrome.

Figure 1

The conventional pathways that generate NADH by breaking down glucose via glycolysis and the Krebs cycle. The enzymes involved in NADH/NAD⁺ recycling are shown. ∗DLDH stands for dihydrolipoamide dehydrogenase and is the component in each given enzyme complex that actually makes NADH from NAD⁺ [191].

Figure 2

NADH oxidation by complex I in the electron transport chain. Electrons from NADH are transported via CoQ and cytochrome c to molecular oxygen. This process involves proton pumping that is tightly linked to superoxide production. ATP synthesis by complex V driven by the proton gradient is also shown.

Figure 3

The branch-off pathways that are activated to dispose excess glucose when glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is inactivated by ROS. These five alternative pathways [21, 115], in addition to the electron transport chain shown in Figure 2, are linked to ROS production, thus further exacerbating oxidative stress. Inset shows the polyol pathway. Pathways in the grey area would no longer efficiently break down glucose when GAPDH is inactivated by posttranslational modifications.

Figure 4

Hyperglycemia induces overproduction of NADH and mitochondrial ROS that inhibit GAPDH activity. This inhibition then activates the alternative glucose metabolic pathways, which further produce ROS involved in glucotoxicity that is responsible for the development of diabetes and diabetic complications. ETC: electron transport chain.