Polyol pathway
Encyclopedia
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.
Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.
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 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 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 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
, myo-inositol, and taurine. Myo-inositol 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 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.
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 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. This change of affinity is what is meant by activation of the pathway. In essence, the Fructose
does the same thing. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.
The 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.
Sorbitol
Sorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
-aldose
Aldose
An aldose is a monosaccharide that contains only one aldehyde group per molecule. The chemical formula takes the form Cnn. The simplest possible aldose is the diose glycolaldehyde, which only contains two carbon atoms....
reductase
Reductase
-Examples:* 5-alpha reductase* Dihydrofolate reductase* HMG-CoA reductase* Methemoglobin reductase* Ribonucleotide reductase* Thioredoxin reductase* E. coli nitroreductase* Methylenetetrahydrofolate reductase...
pathway, the polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and nerves.
Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.
Pathway
Cells use glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
for energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
; however, unused glucose enters the polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
pathway when aldose reductase
Aldose reductase
Aldose reductase is an NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides...
reduces it to sorbitol. This reaction oxidizes NADPH to NADP+. Sorbitol dehydrogenase can then oxidize sorbitol to fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
, which also produces NADH from NAD+. Hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
can return the molecule to the glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
pathway by phosphorylating fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
to form fructose-6-phosphate. However, in uncontrolled diabetics that have high blood glucose - more than the glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
pathway can handle - the reaction's mass balance
Mass balance
A mass balance is an application of conservation of mass to the analysis of physical systems. By accounting for material entering and leaving a system, mass flows can be identified which might have been unknown, or difficult to measure without this technique...
ultimately favors the production of sorbitol.
Activation of the polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
pathway results in a decrease of reduced NADP+ and oxidized NAD+; these are necessary cofactors in redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
reactions throughout the body. The decreased concentration of these cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
s leads to decreased synthesis of reduced glutathione, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, myo-inositol, and taurine. Myo-inositol is particularly required for the normal function of nerves. Sorbitol may also glycate nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
s on proteins, such as collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, 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 cellsCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
require the action of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
for glucose to gain entry into the cell, the cells of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, 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
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
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 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. This change of affinity is what is meant by activation of the pathway. In essence, the Fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
does the same thing. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.
The NADPH acts to promote nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
and glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
production, and its deficiency will cause glutathione deficiency as well. A glutathione deficiency, congenital or acquired, can lead to hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
caused by oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. Nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
is one of the important vasodilators in blood vessels. Therefore NADPH prevents reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
from accumulating and damaging cells.
Excessive activation of the polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
pathway increases intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
and extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
sorbitol concentrations, increased concentrations of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
, and decreased concentrations of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
and glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
. Each of these imbalances can damage cells; in diabetes there are several acting together. It has not been conclusively determined that activating the polyol
Polyol
A polyol is an alcohol containing multiple hydroxyl groups. In two technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry.- Polyols in food science :...
pathway damages microvasculature.
Tertiary references
- Harper's Illustrated Biochemistry(Published by LANGE)
- Dinesh Puri's Medical Biochemistry(Published by ELSEVIER)