| A major barrier in reversing diabetic complications is that molecular and pathological effects of elevated glucose persist despite normalization of glucose, a phenomenon referred to as metabolic memory. In the present studies we have investigated the effects of elevated glucose on Schwann cells, which are implicated in diabetic neuropathy. We have found that chronic (>8wks) but not acute (<2wks) high glucose (25mM) induces a persistent increase in genes that promote glycolysis, while inhibiting those that oppose glycolysis and alternative metabolic pathways, including the pentose phosphate pathway, fatty acid metabolism, and the TCA cycle. These effects of chronic high glucose on metabolic gene expression were sustained despite return to normal 5.6 mM glucose levels, thus exhibiting metabolic memory. These sustained effects were associated with increased oxidative stress, cellular NADH, decreased PPARgamma binding, and altered DNA methylation. We propose that chronic high glucose increases glycolysis, thereby increasing cytoplasmic NADH and oxidative stress in Schwann cells. While PPARgamma agonist was not able to reverse the effects of chronic high glucose on metabolic gene memory, agonists of PPARgamma and PPARalpha prevented select effects of glucose-induced gene expression. These observations suggest that targeting PPAR may prevent metabolic memory and thus facilitate reversal of diabetic complications and offer insight into the role of metabolism in Schwann cells during chronic high glucose and diabetic neuropathy. |
