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The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.
The pathway is implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves.
Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.
Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary co-factors in redox reactions throughout the body, and under normal conditions they are not interchangeable. The decreased concentration of these NADPH leads to decreased synthesis of reduced glutathione, nitric oxide, myo-inositol, and taurine. Myo-inositol is particularly required for the normal function of nerves. Sorbitol may also glycate nitrogens on proteins, such as collagen, and the products of these glycations are referred-to as AGEs - advanced glycation end-products. AGEs are thought to cause disease in the human body, one effect of which is mediated by RAGE (receptor for advanced glycation end-products) and the ensuing inflammatory responses induced. They are seen in the hemoglobin A1C tests performed on known diabetics to assess their levels of glucose control.
In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing much sorbitol to accumulate, and using much more NADPH, leaving less NADPH for other processes of cellular metabolism. This change of affinity is what is meant by activation of the pathway. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.
NADPH acts to promote nitric oxide production and glutathione reduction, and its deficiency will cause glutathione deficiency. A glutathione deficiency, congenital or acquired, can lead to hemolysis caused by oxidative stress. Nitric oxide is one of the important vasodilators in blood vessels. Therefore, NADPH prevents reactive oxygen species from accumulating and damaging cells.
Excessive activation of the polyol pathway increases intracellular and extracellular sorbitol concentrations, increased concentrations of reactive oxygen species, and decreased concentrations of nitric oxide and glutathione. Each of these imbalances can damage cells; in diabetes there are several acting together. It has not been conclusively determined that activating the polyol pathway damages the microvascular systems.
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