Sorbitol pathway activity increases in hyperglycaemia. Which clinical complication is most directly linked to sorbitol accumulation in tissues lacking sorbitol dehydrogenase (lens, nerve, kidney, retina)?
- A Increased oxidative stress through depletion of NADPH
- B Sorbitol competes with glucose for GLUT2, reducing cellular glucose uptake
- C Osmotic damage: sorbitol does not cross cell membranes, accumulates intracellularly causing osmotic injury — diabetic cataract, neuropathy, retinopathy, nephropathy ✓
- D Sorbitol activates PKC, the sole mechanism of vascular complications
Explanation
Aldose reductase converts glucose to sorbitol using NADPH; sorbitol dehydrogenase (absent in lens, Schwann cells, retinal pericytes, mesangial cells) should convert sorbitol to fructose, but without SDH, sorbitol accumulates. Being a large, polar alcohol, sorbitol cannot exit cells freely, raising intracellular osmolarity, causing water influx, cell swelling, and disruption of lens fibre organisation (osmotic cataract), myelin sheath damage (neuropathy), and pericyte loss (retinopathy). NADPH depletion reduces GSH regeneration and is a secondary mechanism. Sorbitol does not use GLUT2. PKC activation is a separate mechanism mediated by diacylglycerol produced from excess glucose.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.