GAPDH and Hyperglycemia: One of the mechanisms proposed for the deleterious effects of hyperglycemia via polyol occurs in the cytosol, which includes a decrease in NADPH, thus diminishing the NADPH/NAD+ ratio and consequently decreasing the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH, a key glycolytic enzyme), causing all glycolytic intermediates that are upstream from GAPDH to increase.