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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,〔Behl T, Kaur I, Kotwani A. Implication of oxidative stress in progression of diabetic retinopathy. Surv Ophthalmol. 2015 Jun 11. pii: S0039-6257(15)00100-9. doi: 10.1016/j.survophthal.2015.06.001. (ahead of print ) Review. PMID 26074354〕 kidney, and nerves.〔Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis. 2015 Jan;6(1):15-28. doi: 10.1177/2040622314552071. Review. PMID 25553239〕
Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.〔Investigative Ophthalmology & Visual Science, Vol 20, 314-326, Copyright © 1981 by Association for Research in Vision and Ophthalmology〕
== Pathway ==
Cells use glucose for energy; however, 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 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 that 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 NADPH and oxidized NAD+; these are necessary cofactors 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 endproducts. AGEs are thought to cause disease in the human body, one effect of which is mediated by RAGE (receptor for advanced glycation endproducts) 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.
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