The polyol pathway

Figure 12.6 The polyol pathway. NADPH, reduced nicotinamide adenine dinucleotide (NAD) phosphate NADH, reduced NAD.

A relationship between polyol pathway activity and reduction in endothelium-dependent relaxation in aorta from chronic STZ-diabetic rats has recently been reported (Cameron and Cotter, 1992). In agreement with several previous studies (Oyama et al., 1986 Kamata et al., 1989), endothelial-dependent relaxation was defective in the diabetic rats but the deficit was prevented by prior treatment with an AR inhibitor. The mechanism underlying the defect has been speculated to be due to decreased production of endothelium-derived relaxing factor (EDRF) or nitric oxide, NO (Hattori et al., 1991). It has been speculated that these vascular abnormalities may lead to diminished blood flow in susceptible tissues and contribute to the development of some diabetic complications. NO is synthesized from the amino-acid L-arginine by a calcium-dependent NO synthase, which requires NADPH as a cofactor. Competition for NADPH from the polyol pathway would take place during times of sustained hyperglycaemia and... 

Outside of the liver, fructose is channeled into the sugar metabolism by reduction at C-2 to yield sorbitol and subsequent dehydration at C-1 to yield glucose (the polyol pathway not shown). 

Extensive evidence exists to suggest a linkage between the pathogenesis of diabetic complications and enhanced glucose metabolism via the polyol pathway. The polyol pathway functions in all tissues susceptible to clinically... 

Schematic of the polyol pathway showing the NADPH-dependent reduction of open chain D-glucose to sorbitol, which is catalyzed by ALR2. This step is followed by the NAD+-dependent oxidation of sorbitol by sorbitol dehydrogenase to yield D-fructose.

The polyol pathway is an active bypass of the dominant glycolysis pathway in many organisms.6 Sorbitol and other polyols such as glycerol, erythritol,... 

In Ayurveda and folklore medicines, cinnamon is used in the treatment of diabetes. Cinnamon is reported to reduce the blood glucose level in non-insulin-dependent diabetics. Therapeutic studies have proved the potential of cinnamaldehyde as an antidiabetic agent. Cinnamaldehyde inhibits aldose reductase, a key enzyme involved in the polyol pathway. This enzyme catalyses the conversion of glucose to sorbitol in insulin-insensitive tissues in diabetic patients. This leads to accumulation of sorbitol in chronic complications of diabetes, such as cataract, neuropathy and retinopathy. Aldose-reductase inhibitors prevent conversion of glucose to sorbitol, thereby preventing several diabetic complications (Lee, 2002). 

Excess glucose can enter the polyol pathway, where it is reduced to sorbitol (by aldose reductase and the reductant NADPH). Sorbitol dehydrogenase will oxidise sorbitol to fructose, which also produces NADH from NAD+. Hexokinase will return fructose to the glycolysis pathway by phosphorylating it to fructose-6-phosphate. However, in uncontrolled diabetics with high blood glucose, the production of sorbitol is favoured. 

Activation of the polyol pathway results in a decrease of NADPH and NAD+ these are necessary cofactors in redox reactions throughout the body. The decreased concentration of these cofactors 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 the amino nitrogen on proteins such as collagen, forming AGEs. 

Some typical structural templates embedded with the thiazoHdine frame have been reported as potent inhibitors of aldose reductase (AR), an enzyme in the polyol pathway responsible for the conversion of glucose to sorbitol. In this, the accumulation of sorbitol has been attributed to causing cataracts, neuropathy, and retinopathy in diabetic cases [ 157,158]. The planar hydrophobic (aromatic) regions and propensity to charge transfer interactions have been... 

Aldose reductase is present in the Schwann cell body but not in the axon. Activation of the polyol pathway depletes myo-inositol and inactivates Na/K-ATPase activity of nerve cells, leading to a reduction in the nerve conduction velocity, at least in diabetic animals, myo-inositol is important for the phosphoinositide-mediated regulation of... 

Loss of mural cells (pericytes) in the retinal microcapillaries is a typical event in diabetic retinopathy. These mural cells contain aldose reductase and accumulate sorbitol in experimental hyperglycaemia (Buzney et al., 1977), leading to degenerative changes implying participation of the polyol pathway in cell death. 

Until the early 1970s there was no understanding of the chemical underpinnings on which the relationship of the preceding pathologies and diabetes rested. They have since been found to be based, at least in part, on abnormalities of glucose metabolism in the diabetic patients. This is referred to as the polyol pathway (Fig. 11-8). 

The enzyme AR and the polyol pathway it initiates was first reported to occur in seminal vesicles. It was soon discovered in the lens. It is now known to exist in many tissues. This and other studies of the eye led to the postulation of the osmotic hypothesis of cataract formation. This polyol concept will be briefly outlined. 

Figure 11-8. The polyol pathway. D-Galactose (4-OH is inverted) is similarly reduced to galacti-col, but it is not further oxidized. Also known as the citric acid cycle. For an excellent chemical and historical review of this most important of metabolic cycles, see Lehninger et al., 1993.

Fig. 29.1. Fructose. The sugar fructose is found in the diet as the free sugar in foods such as honey or as a component of the disaccharide sucrose in fruits and sweets. It also can be synthesized from glucose via the polyol pathway. In the lens of the eye, the polyol pathway contributes to the formation of cataracts. Fructose is metabolized by conversion to intermediates of glycolysis.

Fructose synthesis from glucose in the polyol pathway occurs in seminal vesicles and other tissues. Aldose reductase converts glucose to the sugar alcohol sorbitol (a polyol), which is then oxidized to fructose. In the lens of the eye, elevated levels of sorbitol in diabetes mellitus may contribute to cataract formation. 

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