Increased Polyol Pathway Flux

Aldose reductase is a cytosolic, monomelic oxidoreductase that catalyzes the NADPH-dependent reduction of a wide variety of carbonyl compounds, including glucose. Aldose reductase has a low affinity (high Km) for glucose, and at the normal glucose concentrations found in nondiabetics, the metabolism of glucose by this pathway constitutes a very small percentage of total glucose utilization. However, in a hyperglycemic environment, increased intracellular glucose concentration (and possibly oxidant stress-induced aldose reductase activation) results in increased enzymatic conversion to the polyalcohol sor-bitol. In the polyol pathway, sorbitol is oxidized to fructose by the enzyme sorbitol dehy-drogenase (SDH), with NAD+ reduced to NADH (see Fig. 2).

Ros Type1 Diabetes

Fig. 2. Aldose reductase function and the polyol pathway. Aldose reductase reduces reactive oxygen species (ROS)-generated toxic aldehydes to inactive alcohols, and glucose to sorbitol, using NADPH as a cofactor. Sorbitol dehydrogenase oxidizes sorbitol to fructose using NAD+ as a cofactor (see the text for details). Aldose reductase may be activated by ROS-induced reduction of nitric oxide modification of a cysteine residue in the enzyme's active site. (Adapted from ref. 40.)

Fig. 2. Aldose reductase function and the polyol pathway. Aldose reductase reduces reactive oxygen species (ROS)-generated toxic aldehydes to inactive alcohols, and glucose to sorbitol, using NADPH as a cofactor. Sorbitol dehydrogenase oxidizes sorbitol to fructose using NAD+ as a cofactor (see the text for details). Aldose reductase may be activated by ROS-induced reduction of nitric oxide modification of a cysteine residue in the enzyme's active site. (Adapted from ref. 40.)

It has been proposed that reduction of glucose to sorbitol by NADPH consumes the cofactor NADPH. Because NADPH is required for regenerating reduced glutathione (GSH), this could induce or exacerbate intracellular oxidative stress. Less of the reduced GSH has, in fact, been found in the lens of transgenic mice that overexpress aldose reductase, and this is the most likely mechanism by which increased flux through the polyol pathway has deleterious consequences (41).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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