Polyol pathway

The polyol pathway is a two-step metabolic process that converts glucose into fructose, primarily active in tissues where glucose uptake is insulin-independent, such as the nerves, retina, and kidneys (StatPearls, 2023). The first and rate-limiting step is the reduction of glucose to sorbitol by the enzyme aldose reductase (AR), which utilizes NADPH as a cofactor (PubMed, PMID: 22433098). Subsequently, sorbitol is oxidized to fructose by sorbitol dehydrogenase (SDH) using NAD+ (Wikipedia, 2024). Under chronic hyperglycemic conditions, the increased flux through this pathway leads to the accumulation of intracellular sorbitol, causing osmotic swelling and cellular damage, while the depletion of NADPH impairs the regeneration of glutathione, exacerbating oxidative stress (NIH, 2022). These mechanisms are major contributors to the development of diabetic microvascular complications, including neuropathy, retinopathy, and nephropathy (Nature Reviews Disease Primers, 2019). Therapeutic strategies have focused on developing aldose reductase inhibitors (ARIs) like epalrestat to block this pathway and prevent tissue damage (PubChem, 2024). However, the clinical utility of many ARIs has been limited by safety concerns such as hepatotoxicity and insufficient efficacy in late-stage trials (Journal of Diabetes Investigation, 2013).

Other names

Sorbitol pathwayGlucose-sorbitol pathwayAldose reductase pathway

Inhibition of aldose reductase, the rate-limiting enzyme of the pathway, to prevent the accumulation of sorbitol and the depletion of NADPH and NAD+.