Polyol pathway

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

Inhibitors of AR have been demonstrated to prevent a wide variety of biochemical, functional and structural alterations in animal models of diabetes. Early studies demonstrated arrest of both early cataract development and nerve conduction velocity. At least 30 clinical trials of AR inhibitors have been published involving nearly 1000 patients in total. However, there is little impressive data of their efficacy up to now but, rather than undermine the hypothesis linking excess polyol pathway activity to diabetic complications, it may reflect methodological difficulties and trial design errors. 

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... 

Non-enzymatic glycosylation Polyol pathway Reduced antioxidant resen/e Activated neutrophils, etc. 

Improving giycaemic control may not only reduce the rate of non-enzymatic glycosyiation and monosaccharide autooxidation, but lower polyol pathway activity. In addition, it should have a beneficial effect on other haemodynamic and hormonal factors involved in the development of diabetic vascular disease. However, in studies of diabetic retinopathy, rapid control of glucose levels by intensive insulin therapy has been shown to worsen vascular disease initially and it could be postulated that a sudden improvement in retinal blood flow promotes further free-radical damage as part of a reperfusion-ischaemic injury. 

Cameron, N.E. and Cotter, M.A. (1992) Impaired contraction and relaxation in aorta from streptozocin-diabetic rats role of polyol pathway. Diabetologja 35, 1011-1019. 

McLennan, S., Yue, D.K., Fisher, E., Capogreco, C., HefFernan, S., Ross, G.R. and Turtle, J.R, (1988). Deficiency of ascorbic acid in experimental diabetes relationship with collagen and polyol pathway abnormalities. Diabetes 37, 359-361. 

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.

Lee AY, Chung SS (1999) Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEBJ 13 23-30... 

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

Arun, N. and Nalini, N. (2002) Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods for Fluman Nutrition 5 7(1), 41 -52. 

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 INHIBITORS (ARI) act at the enzyme aldose reductase, which is the first enzyme in the sorbitol (or polyol) pathway which converts glucose to sorbitol. It is thought that in hyperglycaemic states there may be an accumulation of sorbitol, leading to hyperosmotic pathology. ARI agents are under trial for use in the treatment of peripheral diabetic neuropathies, retinopathy and nephropathies. (These include tolrestat. also alrestatin, sorbinil, zenarestat and zopolrestat)... 

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. 

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