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<unk> . When blood glucose is normal (about 100 mg/dl or 5.5 mmol/l), 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. This change of affinity is what is meant by activation of the<unk> . 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<unk>  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<unk>  damages the microvascular systems.
Polyol pathway
Pentose phosphate pathway
Mevalonate pathway
Purine metabolism
Fatty acid metabolism
Pyrimidine metabolism
Mitochondrial biogenesis
Glyceroneogenesis