- Polyol pathway
Also called the
sorbitol -aldose reductase pathway, thepolyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to theretina ,kidney andnerves .The Pathway
Cells use
glucose forenergy , though unusedglucose enters thepolyol pathway whenaldose reductase reduces it tosorbitol . This reaction oxidizesNADPH toNADP+ . Sorbitol dehydrogenase can then oxidizesorbitol tofructose , which also producesNADH fromNAD+ .Hexokinase can return the molecule to theglycolysis pathway byphosphorylating fructose to form fructose-6-phosphate. However, in uncontrolled diabetics who have highblood glucose - more than theglycolysis pathway can handle - the reaction'smass balance ultimately favors the production of sorbitol. Activation of thepolyol pathway results in a decrease of reducedNADP+ and oxidizedNAD+ ; these are necessary cofactors inredox reactions throughout the body. The decreased concentration of thesecofactor s 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 glycatenitrogen s onproteins , such ascollagen , 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.Pathology
While most cells require the action of
insulin forglucose to gain entry into the cell, the cells of theretina ,kidney and nervous tissues areinsulin independent, soglucose moves freely across thecell membrane , regardless of the action ofinsulin . The cells will useglucose forenergy as normal, and anyglucose not used for energy will enter thepolyol pathway. Whenblood glucose is normal (about 100mg/dl or 5.5 mmol/l), this interchange causes no problems, asaldose reductase has a lowaffinity forglucose at normalconcentrations .In a
hyperglycemic state, theaffinity ofaldose reductase forglucose rises, causing muchsorbitol to accumulate, and using much moreNADPH , leaving lessNADPH for other processes ofcellular metabolism cite journal | author=Brownlee M | title=Biochemistry and Molecular Cell Biology of Diabetic Complications | journal=Nature | year=2001 | pages=813–820 | volume=414 | issue=6865 | pmid=: 11742414 [http://bmj.bmjjournals.com/cgi/content/full/320/7246/1373 Full text] | doi=10.1038/414813a] . This change ofaffinity is what is meant by activation of the pathway. Thesorbitol can not crosscell membranes , and when it accumulates, it producesosmotic 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 promotenitric oxide andglutathione production, and its conversion during the pathway leads toreactive oxygen species . Aglutathione deficiency ,congenital or acquired, can lead tohemolysis caused byoxidative stress .Nitric oxide is one of the importantvasodilators in blood vessels.NAD+ preventsreactive oxygen species from damaging cells.Excessive activation of the
polyol pathway increasesintracellular andextracellular sorbitol concentrations , increasedconcentrations ofreactive oxygen species and decreasedconcentrations ofnitric oxide andglutathione . Each of these imbalances can damage cells; indiabetes there are several acting together. It has not been conclusively determined that activating thepolyol pathway damages microvasculature.References
http://www.nature.com/nature/journal/v414/n6865/abs/414813a.html
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