A 66-year-old man comes to the office due to progressive vision impairment over the last year that has begun to affect his ability to drive. He has difficulty reading road signs at night and reports excessive glare from the headlights of oncoming cars. The patient has a long history of hypertension and type 2 diabetes mellitus. Funduscopy reveals a diminished red reflex bilaterally with obscuration of retinal detail. It is determined that the patient's condition is in part due to intracellular accumulation of sorbitol. In healthy cells, this sugar alcohol is normally metabolized into which of the following substances to facilitate excretion?
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This patient has cataracts, a vision-impairing opacification of the lens that causes loss of the red reflex with decreased visualization of retinal details on ophthalmoscopic evaluation. The incidence of cataracts increases with age; other risk factors include smoking, excessive sunlight exposure, diabetes mellitus, and glucocorticoid use. In this patient, long-term hyperglycemia most likely contributed to cataract formation by causing oversaturation of the polyol pathway.
The first step in the polyol pathway (an alternative route of glucose metabolism) is the conversion of glucose into sorbitol by aldose reductase. Sorbitol cannot readily cross cell membranes and is therefore trapped inside the cells where it forms. The second enzyme in the pathway, sorbitol dehydrogenase, is able to convert sorbitol into fructose at a sufficient rate to prevent accumulation when glucose levels are normal. However, the process is slow; in long-standing hyperglycemia, sorbitol accumulates in tissues with lower sorbitol dehydrogenase activity, such as the retina, lens, kidney, and peripheral nerves.
Sorbitol accumulation increases cellular osmotic and oxidative stress and contributes to the pathogenesis of diabetic retinopathy, neuropathy, and nephropathy. In lens cells, the increased stress leads to the development of hydropic lens fibers that degenerate, eventually resulting in lens opacification and cataract formation.
(Choices B and C) Another function of aldose reductase is the conversion of galactose into galactitol (ie, this enzyme converts sugars into their corresponding sugar alcohols). Galactitol production via this pathway is normally insignificant. In galactosemia (galactose-1-phosphate uridyltransferase deficiency), an increased amount of galactitol is produced, resulting in congenital cataracts.
(Choice D) The end product of sorbitol metabolism in most cells is fructose (not glucose), which is then excreted by the cells and taken up by the liver to produce glucose and triglycerides.
(Choice E) Xylulose is an intermediate in the pentose phosphate pathway, which is used to generate NADPH (for cholesterol and fatty acid synthesis) and ribose 5-phosphate (for nucleotide synthesis).
Educational objective:
In the polyol pathway, aldose reductase converts glucose into sorbitol, which is slowly metabolized into fructose by sorbitol dehydrogenase. Chronic hyperglycemia overwhelms this pathway, causing intracellular sorbitol accumulation and increased osmotic/oxidative stress. This accelerates cataract development in patients with diabetes, and contributes to the pathogenesis of diabetic retinopathy, neuropathy, and nephropathy.