Polyol pathway

Also called the sorbitol-aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney and nerves.

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The Pathway

Cells use glucose for energy, though unused glucose enters the polyol pathway when aldose reductase reduces it to sorbitol. This reaction oxidizes NADPH to NADP+. Sorbitol dehydrogenase can then oxidize sorbitol to fructose, which also produces NADH from NAD+. Hexokinase can return the molecule to the glycolysis pathway by phosphorylating fructose to form fructose-6-phosphate. However, in uncontrolled diabetics who have high blood glucose - more than the glycolysis pathway can handle - the reaction's mass balance ultimately favors the production of sorbitol.

Activation of the polyol pathway results in a decrease of reduced NADP+ and oxidized NAD+; these are necessary cofactors in redox reactions throughout the body. The decreased concentration of these cofactors leads to decreased synthesis of reduced glutathione, nitric oxide, myoinositol, and taurine. Myoinositol 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 endproducts. AGEs are thought to cause disease in the human body, one effect of which is mediated by receptor mediators cytokines effects (?) and the inflammatory responses induced, and these are seen in the hemoglobin A1C tests performed on known diabetics to assess their levels of glucose control.

Pathology

While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway. When blood glucose is normal (about 100 mg/dl), this interchange causes no problems, as aldose reductase has a low affinity for glucose at normal concentrations.

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^[1]. This change of affinity is what is meant by activation of the pathway. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water in. Fructose does essentially the same thing. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.

The NADPH acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen species. 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. NAD+ prevents reactive oxygen species from 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 microvasculature.

References

http://www.nature.com/nature/journal/v414/n6865/abs/414813a.html

1. ^ Brownlee M (2001). "Biochemistry and Molecular Cell Biology of Diabetic Complications". Nature 414 (6865): 813-820. PMID: 11742414 Full text.