Thepolyol pathway is a two-step process that converts glucose to fructose.[1] In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called thesorbitol-aldose reductase pathway.
The pathway is implicated indiabetic complications, especially in microvascular damage to theretina,[2]kidney,[3] andnerves.[4]
Sorbitol cannot crosscell membranes, and, when it accumulates, it producesosmotic stresses on cells by drawing water into the insulin-independent tissues.[5]
Cells useglucose forenergy. This normally occurs by phosphorylation from the enzyme hexokinase. However, if large amounts of glucose are present (as indiabetes mellitus), hexokinase becomes saturated and the excess glucose enters thepolyol pathway whenaldose reductase reduces it to sorbitol. This reaction oxidizesNADPH toNADP+.Sorbitol dehydrogenase can then oxidize sorbitol tofructose, which producesNADH fromNAD+.Hexokinase can return the molecule to theglycolysis pathway byphosphorylating fructose to form fructose-6-phosphate. However, in uncontrolled diabetics that have highblood glucose - more than the glycolysis pathway can handle - the reactionsmass balance ultimately favors the production of sorbitol.[6]
Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary co-factors inredox reactions throughout the body, and under normal conditions they arenot interchangeable. The decreased concentration of these NADPH leads to decreased synthesis ofreduced glutathione,nitric oxide,myo-inositol, andtaurine. Myo-inositol is particularly required for the normal function of nerves. Sorbitol may also glycate nitrogens onproteins, such ascollagen, 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 thehemoglobin A1C tests performed on known diabetics to assess their levels of glucose control.[6]
While most cells require the action ofinsulin for glucose to gain entry into the cell, the cells of theretina,kidney, and nervous tissues are insulin-independent, so glucose moves freely across thecell 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. Whenblood glucose is normal (about 100 mg/dL or 5.5 mmol/L), this interchange causes no problems, as aldose reductase has a lowaffinity for glucose at normalconcentrations.[citation needed]
In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing much sorbitol to accumulate, and using much moreNADPH, leaving less NADPH for other processes ofcellular metabolism.[7] 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 promotenitric oxide production andglutathione reduction, and its deficiency will cause glutathione deficiency. Aglutathione deficiency,congenital or acquired, can lead tohemolysis caused byoxidative stress. Nitric oxide is one of the importantvasodilators in blood vessels. Therefore, NADPH preventsreactive oxygen species from accumulating and damaging cells.[6]
Excessive activation of the polyol pathway increasesintracellular andextracellular 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.[6]