High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aorticendothelial cells

Recent studies have shown that hyperglycemia is a principal cause of cellul ar damage in patients with diabetes mellitus, A major consequence of hyperg lycemia is increased oxidative stress. Glucose-8-phosphate dehydrogenase (G 6PD) plays an essential role in the regulation of oxidative stress by prima rily regulating NADPH, the main intracellular reductant. In this paper we s how that increased glucose (10-25 mM) caused inhibition of G6PD resulting i n decreased NADPH levels in bovine aortic endothelial cells (BAEC), Inhibit ion was seen within 15 min. High glucose-induced inhibition of G6PD predisp osed cells to cell death. High glucose via increased activity of adenylate cyclase also stimulated an increase in cAMP levels in BAEC. Agents that inc reased cAMP caused a decrease in G6PD activity. Inhibition of cAMP-dependen t protein kinase A ameliorated the high glucose-induced inhibition of G6PD, Finally, high glucose stimulated phosphorylation of G6PD. These results su ggest that, in BAEC, high glucose stimulated increased cAMP, which led to i ncreased protein kinase A activity, phosphorylation of G6PD, and inhibition of G6PD activity. We conclude that these changes in G6PD activity play an important role in high glucose-induced cell damage/death.