Polyol pathway

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The polyol pathway is a two-step process that converts glucose to fructose. [1] In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

Contents

The pathway is implicated in diabetic complications, especially in microvascular damage to the retina, [2] kidney, [3] and nerves. [4]

Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues. [5]

Pathway

The polyol metabolic pathway. Polyol metabolic pathway.png
The polyol metabolic pathway.

Cells use glucose for energy. This normally occurs by phosphorylation from the enzyme hexokinase. However, if large amounts of glucose are present (as in diabetes mellitus), hexokinase becomes saturated and the excess 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 reactions mass balance ultimately favors the production of sorbitol. [6]

Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary co-factors 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 end-products. AGEs are thought to cause disease in the human body, one effect of which is mediated by RAGE (receptor for advanced glycation end-products) 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. [6]

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. [7] 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. [6]

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 the microvascular systems. [6]

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Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.

<span class="mw-page-title-main">Sorbitol</span> Chemical compound

Sorbitol, less commonly known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcohol group (−CH2OH). Most sorbitol is made from potato starch, but it is also found in nature, for example in apples, pears, peaches, and prunes. It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.

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<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

<span class="mw-page-title-main">Sorbitol dehydrogenase</span> Enzyme

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<span class="mw-page-title-main">Epalrestat</span> Chemical compound

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<span class="mw-page-title-main">Sorbinil</span> Chemical compound

Sorbinil (INN) is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy. Aldose reductase is an enzyme present in lens and brain that removes excess glucose by converting it to sorbitol. Sorbitol accumulation can lead to the development of cataracts in the lens and neuropathy in peripheral nerves. Sorbinil has been shown to inhibit aldose reductase in human brain and placenta and calf and rat lens. Sorbinil reduced sorbitol accumulation in rat lens and sciatic nerve of diabetic rats orally administered 0.25 mg/kg sorbinil.

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Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

Pseudohypoxia refers to increased cytosolic ratio of free NADH/NAD+ ratio in cells, where NADH is overly increased and NAD+ is overly decreased. It can be caused by diabetic hyperglycemia and by excessive alcohol consumption. The insufficiency of available NAD+ produces symptoms similar to hypoxia (lack of oxygen), because NAD+ is primarily needed by the Krebs cycle for oxidative phosphorylation, and to a lesser extent is needed in anaerobic glycolysis. Oxidative phosphorylation and glyocolysis are vital as these metabolic pathways produce ATP, which is the molecule that releases energy necessary for cells to function.

References

  1. ↑ Bonnefont-Rousselot D (September 2002). "Glucose and reactive oxygen species". Current Opinion in Clinical Nutrition and Metabolic Care. 5 (5): 561–8. doi:10.1097/00075197-200209000-00016. PMID   12172481. S2CID   20485164.
  2. ↑ Behl T, Kaur I, Kotwani A (2016). "Implication of oxidative stress in progression of diabetic retinopathy". Survey of Ophthalmology. 61 (2): 187–96. doi:10.1016/j.survophthal.2015.06.001. PMID   26074354.
  3. ↑ Forbes JM, Coughlan MT, Cooper ME (June 2008). "Oxidative stress as a major culprit in kidney disease in diabetes". Diabetes. 57 (6): 1446–54. doi: 10.2337/db08-0057 . PMID   18511445.
  4. ↑ Javed S, Petropoulos IN, Alam U, Malik RA (January 2015). "Treatment of painful diabetic neuropathy". Therapeutic Advances in Chronic Disease. 6 (1): 15–28. doi:10.1177/2040622314552071. PMC   4269610 . PMID   25553239.
  5. ↑ Jedziniak JA, Chylack LT, Cheng HM, Gillis MK, Kalustian AA, Tung WH (March 1981). "The sorbitol pathway in the human lens: aldose reductase and polyol dehydrogenase". Investigative Ophthalmology & Visual Science. 20 (3): 314–26. PMID   6782033.
  6. 1 2 3 4 5 Michael Brownlee (2005). "The pathobiology of diabetic complications: A unifying mechanism". Diabetes. 54 (6): 1615–1625. doi: 10.2337/diabetes.54.6.1615 . PMID   15919781.
  7. ↑ Brownlee M (December 2001). "Biochemistry and molecular cell biology of diabetic complications". Nature. 414 (6865): 813–20. Bibcode:2001Natur.414..813B. doi:10.1038/414813a. PMID   11742414. S2CID   4396508.

Further references

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