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 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 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. == References ==