Nad Nadh

Figure 2 Sorbitol oxidation increases cytosolic NADH/NAD+, which is linked to hyperglycemic pseudohypoxia (11).

NAD+ enhances the synthesis of prostaglandins, which leads to free radical production. Further, the oxidation of NADH to NAD+ in the electron transport chain in the mitochondria involves increased production of superoxide radical

The superoxide radical is normally catalyzed by superoxide dismutase to hydrogen peroxide. The iron-dependent Fenton reaction leads to the aggressive hydrogen peroxide radical that further attacks the side chains of lipids,

Prostaglandin synthesis # NADH^* NAD+

Figure 3 Hyperglycemia activates the sorbitol pathway. Sorbitol oxidation increases cytosolic NADH/NAD+. Increased NADH/NAD+ ratios increase prostaglandin synthesis, leading to free radical production. In the mitochondria, the superoxide radical is generated by oxidation of NADH in the electron transport chain.

Hyperglycemia Sorbitol pathway activity %

NADH/NAD+ t

oxidation in mitochondria

h2o2

oh"

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