Joseph R Williamson and Yasuo Ido
Significance: Numerous clinical trials implicate a key role for hyperglycemia in the pathogenesis of diabetic complications. Recent studies support the importance of oxidative stress in mediating these complications. Although it is well known that hyperglycemia increases the rates of glucose metabolism via glycolysis and the sorbitol pathway, the importance of their contributions to oxidative stress and diabetic complications remains controversial.
Recent advances and critical issues: The major objectives of this review are to draw attention to: 1) recent advances supporting the importance of oxidative stress linked to increased sorbitol oxidation in fueling oxidative stress evoked by hyperglycemia, 2) important caveats to interpretations of experimental observations using flawed experimental protocols and methods and/or inappropriate surrogate animal models of diabetes (i.e. galactosemia) thought to challenge or refute an important role for the sorbitol pathway in the pathogenesis of diabetic complications and 3) speculations not supported by credible evidence.
The first enzyme in the sorbitol pathway is Aldose Reductase (AR), which converts glucose to sorbitol. Sorbitol is then reduced to fructose by Sorbitol Dehydrogenase (SDH) coupled to transfer of electrons and protons to oxidized cytoplasmic Nicotinamide Adenine Dinucleotide (NAD+c) to form NADHc, the reduced form of NAD. NADHc fuels production of superoxide by NADHc-fueled NAD(P)H oxidases causing oxidative stress which impairs the activity of numerous enzymes including Na+K+/ATPase resulting in Metabolic Suppression. Oxidative stress and Metabolic Suppression play key roles in mediating diabetic complications.
Future directions: This scenario has important implications for the design and optimization of future therapies for prevention and treatment of diabetic complications, e.g. endogenous antioxidants C-peptide and pyruvate and more efficacious inhibitors of sorbitol production and sorbitol oxidation.