In uncontrolled diabetes mellitus, glucose levels in lens, nerve, and retinal vessels exceed the Km of hexokinase, diverting glucose into the polyol pathway. What is the direct biochemical consequence of this diversion that contributes to cataract formation?

• A Excessive production of NADPH that over-reduces glutathione pools
• B Accumulation of intracellular sorbitol with osmotic swelling and depletion of NADPH ✓
• C Depletion of ATP due to consumption of two high-energy phosphates per glucose
• D Accumulation of fructose-6-phosphate, which cross-links crystallins directly

Explanation

Aldose reductase reduces glucose to sorbitol using NADPH, and sorbitol dehydrogenase then converts sorbitol to fructose using NAD+. In hyperglycemia, sorbitol accumulates because sorbitol dehydrogenase has low affinity for it and sorbitol crosses membranes poorly, causing osmotic stress in lens fibers. The pathway also consumes NADPH, reducing glutathione regeneration and antioxidant defense. Option C describes glycolysis energetics, not the polyol pathway.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.