Figure 1: Key roles of increased cytosolic NADHc produced by sorbitol oxidation in fueling superoxide formation and related metabolic pathways linked to the pathogenesis of diabetic complications.
The percentage increase in sorbitol oxidation in normal rat retinas and endoneuria incubated in 30 vs. 5 mM glucose (manifested by production of fructose equimolar to NADHc) exceeds the percent increase in glycolysis (manifested by lactate production) [27,80].
Since oxidation of sorbitol does not form pyruvate, NADHc levels rise ~1.5-2-fold (manifested by increased ratios of NADH/NAD+c=lactate/pyruvate × KLDH) [44], fructose levels increase (~10-30-fold), and much more NADHc is reoxidized to NAD+c via alternative pathways, i.e. by NADHc-fueled NAD(P)H oxidases that increase superoxide production and by G3P-DHc which increases synthesis of diacylglycerol (DAG) [25-57] which activates protein kinase C (PKC) that activates NADPH-driven oxidases to further augment superoxide production. The ~1.5-2-fold increases in NADHc also contribute to product inhibition of GA3P-DH, which increases levels of GA3P and DHAP, i.e. triose phosphates- TPs, [25] that are in equilibrium. Non-enzymatic degradation of DHAP and GA3P forms methylglyoxal (MG), a precursor of advanced glycation endproducts (AGEs) that impair the activity of numerous enzymes including GA3PDH [25,61,62].