Polyol Pathway and Protein Kinase C Activation

Hyperglycemia activates the polyol pathway, resulting in the formation of sorbitol by aldose reductase. As aldose reductase utilizes NADPH for the reduction of glucose to sorbitol, cellular stores of NADPH may be depleted (55). NADPH is required for the functioning of several enzymes, such as NO, synthase for NO generation, and cytochromes P450, and for the activity of glutathione reductase that replenishes glutathione, one of the most important endogenous antioxidant systems. Increased polyol pathway activity is associated with the occurrence of long-term complications in patients with diabetes. This is demonstrated by the efficacy of aldose reductase inhibitors in the restoration of impaired endothelium-dependent vasodilatation, as well as in the prevention of diabetic neuropathy, albuminuria, and cataracts in animal models but so far not in humans.

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