Alternative glucose pathway active in tissues with insulin-independent glucose uptake (lens, retina, peripheral nerve, kidney). Glucose → sorbitol (aldose reductase, NADPH consumer) → fructose (sorbitol dehydrogenase, NAD+ consumer). Hyperglycemia drives flux through this pathway, producing osmotic stress (sorbitol accumulation), NADPH depletion (oxidative stress; impaired glutathione regeneration), and AGE precursor generation (fructose is more reactive than glucose). Proposed mechanism for diabetic neuropathy, retinopathy, cataracts. Aldose reductase inhibitors (epalrestat, ranirestat) developed for diabetic neuropathy with mixed clinical outcomes — epalrestat approved in Japan + China but not in Western markets.
Organ Systems
endocrine
nervous
renal
Pathway Steps
glucose → sorbitol — via aldose reductase (AKR1B1) — NADPH consumer; EPALRESTAT TARGET. Aldose reductase reduces glucose to sorbitol using NADPH; normally minor, it surges in hyperglycemia in insulin-independent tissues (lens, nerve, retina, kidney). NADPH consumption depletes glutathione (oxidative stress) and trapped sorbitol causes osmotic injury — diabetic cataract/neuropathy (epalrestat targets it).
sorbitol → fructose — via sorbitol dehydrogenase (SORD) — NAD+ consumer. Sorbitol dehydrogenase oxidizes sorbitol to fructose, consuming NAD⁺ (raising NADH much as ethanol does). The added fructose and altered redox compound the polyol pathway’s role in diabetic tissue injury; this route also makes seminal fructose.