Sorbitol pathway

It seems to be important to avoid high intracellular concentrations of free glucose. Most probably because it can activate the so-called sorbitol pathway and generate advanced glycosylation endpoints [91]. It is therefore helpful that not only glucose uptake, but also the phosphorylation and removal of G6P are stimulated by insulin [92]. 

Diabetics are also damaged by another consequence of hyperglycemia increased metabolism by the sorbitol pathway. In some cells that do not require insulin for glucose uptake (e.g., Schwann cells in... 

Harkdnen. M., and Tarkkaneit. A. (1976). Effects of phospholinc iodide on the metabolites of the glycolytic pentose phosphate and sorbitol pathways in the rabbit lens. Acta OpiuhalmoL 54, 445-455. 

That seminal fructose may be formed by the sorbitol pathway was first postulated by Williams-Ashman and Banks (252) on the basis of their studies on the distribution of sorbitol dehydrogenase in various rodent male accessory glands. Shortly afterwards. Hers (253,254) discovered an NADPH-specific aldose reductase that reduced glucose to sorbitol and proposed that the overall synthesis of fructose from glucose occurs according to the following equations ... 

In these coupled reactions, the overall transformation of glucose to fructose is accompanied by a transfer of hydrogen from NADPH to NAD. Studies on the activity of aldose reductase and sorbitol dehydrogenase as well as the presence of sorbitol in seminal vesicles of several species and rat coagulating gland are consistent with the operation of the sorbitol pathway as a major determinant of seminal fructose biosynthesis (248, 252-260). Nonphosphorylative conversion of glucose to sorbitol has also been demonstrated in placenta (258, 261, 262), smooth muscle of the aorta (263), the lens of the eye (264, 265), erythrocytes (266) and hepatoma-derived (HTC) cells in culture (267), and possibly normal liver cells (267, 268). 

Animal studies have shown that in vivo F MRS can be used in metabolic studies. It has been shown that 3-fluoro-3-deoxy-D-glucose in the brain is metabolized primarily in the aldose reductase sorbitol pathway, suggesting that F MRS may be a useful tool for the further elucidation of this pathway. Further studies have shown that it is also possible to study the metabolism of fluorinated galactose, tryptophan and protein in vivo and determine intracellular calcium levels. The concentration of this cation was shown to be the same in the kidney, spleen and brain of rats, at approximately 200 nM. These measurements were obtained by infusing the calcium indicator 5F-BAPTA (=5,5-difluoro-l,2-bis(o-amino-phenoxy)ethane-N, N, M, A/ -tetraacetic acid) intravenously or intraventricularly into the animal, and so the potential application to human subjects appears limited. 

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). 

Figure6.8 Reaction pathways involved in glucose and sorbitol reforming (adapted from Ref [274]).

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. 

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