Sorbitol (aldose reductase) pathway flux in diabetes perturbs intracellular metabolism by two putative mechanisms: recipro- cal osmoregulatory depletion of other organic osmolytes e.g., myo-inositol, and alterations in NADPH/NADP+ and/or NADH/NAD'. The "osmolyte" and "redox" hypotheses pre- dict secondary elevations in CDP-diglyceride, the rate-limiting precursor for phosphatidylinositol synthesis, but through dif- ferent mechanisms: the "osmolyte" hypothesis via depletion of intracellular myo-inositol (the cosubstrate for phosphatidylino- sitolsynthase) and the "redox" hypothesis through enhanced de novo synthesis from triose phosphates. The osmolyte hy- pothesis predicts diminished phosphoinositide-derived arachi- donyldiacylglycerol, while the redox hypothesis predicts in- creased total diacylglycerol and phosphatidic acid. In high al- dose reductase expressing retinal pigment epithelial cells, glucose-induced, aldose reductase inhibitor-sensitive CDP-di- glyceride accumulation and inhibition of32P-incorporation into phosphatidylinositol paralleled myo-inositol depletion (but not cytoplasmic redox, that was unaffected by glucose) and deple- tion ofarachidonyl-diacylglycerol. 3 mMpyruvate added to the culture medium left cellular redox unaltered, but stimulated Na+-dependent myo-inositol uptake, accumulation, and incor- poration into phosphatidylinositol. These results favor myo-in- ositol depletion rather than altered redox as the primary cause ofglucose-induced aldose reductase-related defects in phospho- lipid metabolism in cultured retinal pigment epithelial cells.
Effects of glucose on sorbitol pathway activation, cellular redox, and metabolism of myo-inositol, phosfhoinositide, and diacylglycerol in cultured human retinal pigment epitelial cells
PORCELLATI, Francesca;
1994
Abstract
Sorbitol (aldose reductase) pathway flux in diabetes perturbs intracellular metabolism by two putative mechanisms: recipro- cal osmoregulatory depletion of other organic osmolytes e.g., myo-inositol, and alterations in NADPH/NADP+ and/or NADH/NAD'. The "osmolyte" and "redox" hypotheses pre- dict secondary elevations in CDP-diglyceride, the rate-limiting precursor for phosphatidylinositol synthesis, but through dif- ferent mechanisms: the "osmolyte" hypothesis via depletion of intracellular myo-inositol (the cosubstrate for phosphatidylino- sitolsynthase) and the "redox" hypothesis through enhanced de novo synthesis from triose phosphates. The osmolyte hy- pothesis predicts diminished phosphoinositide-derived arachi- donyldiacylglycerol, while the redox hypothesis predicts in- creased total diacylglycerol and phosphatidic acid. In high al- dose reductase expressing retinal pigment epithelial cells, glucose-induced, aldose reductase inhibitor-sensitive CDP-di- glyceride accumulation and inhibition of32P-incorporation into phosphatidylinositol paralleled myo-inositol depletion (but not cytoplasmic redox, that was unaffected by glucose) and deple- tion ofarachidonyl-diacylglycerol. 3 mMpyruvate added to the culture medium left cellular redox unaltered, but stimulated Na+-dependent myo-inositol uptake, accumulation, and incor- poration into phosphatidylinositol. These results favor myo-in- ositol depletion rather than altered redox as the primary cause ofglucose-induced aldose reductase-related defects in phospho- lipid metabolism in cultured retinal pigment epithelial cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
