https://www.wikidoc.org/index.php?title=Polyol_pathway&feed=atom&action=historyPolyol pathway - Revision history2024-03-28T11:24:18ZRevision history for this page on the wikiMediaWiki 1.40.0https://www.wikidoc.org/index.php?title=Polyol_pathway&diff=723927&oldid=prevWikiBot: Robot: Automated text replacement (-{{reflist}} +{{reflist|2}}, -<references /> +{{reflist|2}}, -{{WikiDoc Cardiology Network Infobox}} +)2012-09-06T13:57:44Z<p>Robot: Automated text replacement (-{{reflist}} +{{reflist|2}}, -<references /> +{{reflist|2}}, -{{WikiDoc Cardiology Network Infobox}} +)</p>
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Also called the '''[[sorbitol]]-aldose reductase pathway''', the [[polyol]] pathway appears to be implicated in diabetic complications, especially in microvascular damage to the [[retina]], [[kidney]] and [[nerves]]. <br />
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== The Pathway ==<br />
Cells use [[glucose]] for [[energy]], though 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 also 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 who have high [[blood glucose]] - more than the [[glycolysis]] pathway can handle - the reaction's [[mass balance]] ultimately favors the production of sorbitol.<br />
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Activation of the [[polyol]] pathway results in a decrease of reduced [[NADP+]] and oxidized [[NAD+]]; these are necessary cofactors in [[redox]] reactions throughout the body. The decreased concentration of these [[cofactor]]s leads to decreased synthesis of [[reduced glutathione]], [[nitric oxide]], [[myoinositol]], and [[taurine]]. [[Myoinositol]] is particularly required for the normal function of nerves. [[Sorbitol]] may also glycate [[nitrogen]]s 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 receptor mediators cytokines effects (?) and the inflammatory responses induced, and these are seen in the hemoglobin A1C tests performed on known diabetics to assess their levels of glucose control.<br />
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== Pathology ==<br />
While most [[Cell (biology)|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]]), this interchange causes no problems, as [[aldose reductase]] has a low [[affinity]] for [[glucose]] at normal [[concentrations]]. <br />
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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]]<!--<br />
--><ref name="BrownleeNature2001">{{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 | id=PMID: 11742414 [http://bmj.bmjjournals.com/cgi/content/full/320/7246/1373 Full text]}}</ref>. This change of [[affinity]] is what is meant by activation of the pathway. The [[sorbitol]] can not cross [[cell membranes]], and when it accumulates, it produces [[osmotic]] 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.<br />
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The [[NADPH]] acts to promote [[nitric oxide]] and [[glutathione]] production, and its conversion during the pathway leads to [[reactive oxygen species]]. 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. [[NAD+]] prevents [[reactive oxygen species]] from damaging cells.<br />
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Excessive activation of the [[polyol]] pathway 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 [[polyol]] pathway damages microvasculature.<br />
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==References==<br />
http://www.nature.com/nature/journal/v414/n6865/abs/414813a.html<br />
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[[Category:Chemical pathology]]<br />
[[Category:Metabolic pathways]]<br />
[[Category:Diabetes]]<br />
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