AMBIENT GLUCOSE AND ALDOSE REDUCTASE-INDUCED MYOINOSITOL DEPLETION MODULATE BASAL AND CARBACHOL-STIMULATED INOSITOL PHOSPHOLIPID-METABOLISMAND DIACYLGLYCEROL ACCUMULATION IN HUMAN RETINAL-PIGMENT EPITHELIAL-CELLS IN CULTURE

Physiological hyperglycemia has been speculated to alter phosphoinosit ide (PPI; inositol phospholipid) signal transduction in cells prone to diabetic complications by two separate mass-action mechanisms with an tiparallel putative effects on diacylglycerol (DAG): (i) sorbitol-indu ced depletion of myo-inositol leads to diminished PPI synthesis and tu rnover and DAG release, and (ii) elevated glucose-derived DAG precurso rs enhance de novo DAG synthesis. Because the first mechanism is media ted by aldose reductase (AR2), which converts glucose to sorbitol, the effects of glucose on basal and stimulated PPI signaling were explore d in lines of cultured human retinal pigment epithelial cells differin g widely in their basal AR2 gene expression and enzymatic activity. Th e results suggest that the effects of glucose on PPI signaling vary in versely with the level of AR2 activity and parallel the extent of AR2- induced myo-inositol depletion.