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a trodden path (同)footpath

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道,小道(path)
=polytechnic

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/04 00:43:45」(JST)

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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,^[1] kidney,^[2] and nerves.^[3]

Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.^[4]

Pathway

The polyol metabolic 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.

Pathology

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.^[5] 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 and glutathione production, and its deficiency will cause glutathione deficiency as well. 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 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.

Notes

^ 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. [Epub ahead of print] Review. PMID 26074354
^ Forbes, JM; Coughlan MT; Cooper ME (June 2008). "Oxidative stress as a major culprit in kidney disease in diabetes". Diabetes 57 (6): 1446–1454. doi:10.2337/db08-0057. PMID 18511445.
^ 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
^ Investigative Ophthalmology & Visual Science, Vol 20, 314-326, Copyright © 1981 by Association for Research in Vision and Ophthalmology
^ Brownlee M (2001). "Biochemistry and Molecular Cell Biology of Diabetic Complications". Nature 414 (6865): 813–820. doi:10.1038/414813a. PMID 11742414.

References

[1]

Further references

Harper's Illustrated Biochemistry(Published by LANGE)
Dinesh Puri's Medical Biochemistry(Published by ELSEVIER)

UpToDate Contents

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English Journal

Inhibitor selectivity between aldo-keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111).

Zhang L, Zhang H, Zhao Y, Li Z, Chen S, Zhai J, Chen Y, Xie W, Wang Z, Li Q, Zheng X, Hu X.SourceSchool of Pharmaceutical Sciences, Centre for Cellular and Structural Biology of Sun Yat-sen University, Guangzhou 510006, China.
FEBS letters.FEBS Lett.2013 Nov 15;587(22):3681-6. doi: 10.1016/j.febslet.2013.09.031. Epub 2013 Oct 4.
The antineoplastic target aldo-keto reductase family member 1B10 (AKR1B10) and the critical polyol pathway enzyme aldose reductase (AKR1B1) share high structural similarity. Crystal structures reported here reveal a surprising Trp112 native conformation stabilized by a specific Gln114-centered hydro
PMID 24100137

Weak protein-protein interactions revealed by immiscible filtration assisted by surface tension (IFAST).

Berry SM, Chin EN, Jackson SS, Strotman LN, Goel M, Thompson NE, Alexander CM, Miyamoto S, Burgess RR, Beebe DJ.SourceDepartments of Biomedical Engineering, University of Wisconsin-Madison. Electronic address: scott.michael.berry@gmail.com.
Analytical biochemistry.Anal Biochem.2013 Nov 8. pii: S0003-2697(13)00526-5. doi: 10.1016/j.ab.2013.10.038. [Epub ahead of print]
Biological mechanisms are often mediated by transient interactions between multiple proteins. The isolation of intact protein complexes is essential to understanding biochemical processes and an important prerequisite for identifying new drug targets and biomarkers. However, low-affinity interaction
PMID 24215910

From the Gastrointestinal Tract (GIT) to the Kidneys: Live Bacterial Cultures (Probiotics) Mediating Reductions of Uremic Toxin Levels via Free Radical Signaling.

Vitetta L, Linnane AW, Gobe GC.SourceThe University of Queensland, School of Medicine, Brisbane, St Lucia QLD 4072, Australia. l.vitetta@uq.edu.au.
Toxins.Toxins (Basel).2013 Nov 7;5(11):2042-57. doi: 10.3390/toxins5112042.
A host of compounds are retained in the body of uremic patients, as a consequence of progressive renal failure. Hundreds of compounds have been reported to be retention solutes and many have been proven to have adverse biological activity, and recognized as uremic toxins. The major mechanistic overv
PMID 24212182