Sorbitol Polyol Pathway

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 

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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). 

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 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)... 

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. 

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. 

Fructose can be synthesized from glucose in the polyol pathway. The polyol pathway is named for the first step of the pathway in which sugars are reduced to the sugar alcohol by the enzyme aldose reductase (Fig. 29.4) Glucose is reduced to the sugar alcohol sorbitol, and sorbitol is then oxidized to fructose. 

The polyol pathway of sorbitol production and the HMP shunt pathway are linked by which of the following ... 

Polyol Pathway. Recently, theories and data have been emerging which implicate aldose reductase (AR), increased flux through the polyol pathway due to hyperglycemia and accumulation of sorbitol and fructose in the pathophysiology of diabetic complications. The biological rationale and chemical progress towards design of AR inhibitors constitute the major focus of this review. 

The polyol pathway consists of two enzymes, AR and sorbitol dehydrogenase. AR has a rather broad substrate specificity for sugars and a fairly high Km for glucose.These two enzymes catalyze the following reactions ... 

Tissue Location and Role of Aldose Reductase in Animal Models of Diabetic Complications. Aldose reductase (AR) has been located immunohistochemically in many tissues of the dog and rat, most notably, in corneal epithelium, retina, optic nerve, kidney papillae, aortic endothelium and smooth muscle cells as well as peripheral nerve and lens. AR has also been measured in human and monkey retinal mural cells. These cells are thought to provide the structural support for retinal capillaries and their loss is the first abnormality seen in clinical diabetic retinopathy. In addition, AR-like activity has been reported in a human retinoblastoma cell line and sorbinil inhibits this activity in these cells. Finally, a recent report has demonstrated that AR is present in isolated capillaries from bovine retina and cerebral cortex. Therefore, AR appears to be present in all tissues which are uniquely susceptible to deterioration during prolonged exposure to the hyperglycemia of diabetes. Accumulation of the products of the polyol pathway, sorbitol and fructose, has been demonstrated in these tissues and, where tested, sorbinil and other AR inhibitors have been shown to inhibit this accumulation. 

Aldose reductase inhibitors (ARI) reduce the flux of glucose through the polyol pathway thereby inhibiting the accumulation of sorbitol and fructose and preventing NADPH consumption and oxidative stress. Numerous studies of ARI in animal models of diabetic complications have demonstrated the potential of ARI against diabetic neuropathy. However, animal models of neuropathy do not predict outcome in human beings well. 

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