title: Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists.
abstract: A major barrier in reversing diabetic complications is that molecular and pathologic 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. Using quantitative PCR arrays for glucose and fatty acid metabolism, we have found that chronic (>8 wk) 25 mM high glucose induces a persistent increase in genes that promote glycolysis, while inhibiting those that oppose glycolysis and alternate metabolic pathways such as fatty acid metabolism, the pentose phosphate pathway, and trichloroacetic acid cycle. These sustained effects were associated with decreased peroxisome proliferator-activated receptor (PPAR)γ binding and persistently increased reactive oxygen species, cellular NADH, and altered DNA methylation. Agonists of PPARγ and PPARα prevented select effects of glucose-induced gene expression. These observations suggest that Schwann cells exhibit features of metabolic memory that may be regulated at the transcriptional level. Furthermore, targeting PPAR may prevent metabolic memory and the development of diabetic complications.
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mt Sinai School, New York, New York 10029, USA.
authors.forename: Esther S
authors.initials: ES
authors.lastname: Kim
authors.forename: Fumiko
authors.initials: F
authors.lastname: Isoda
authors.forename: Irwin
authors.initials: I
authors.lastname: Kurland
authors.forename: Charles V
authors.initials: CV
authors.lastname: Mobbs
mesh_terms: D000818:Animals; D002460:Cell Line; D002952:Citric Acid Cycle / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000517:prevention & control; D004734:Energy Metabolism / Q000187:drug effects*; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D009419:Nerve Tissue Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D005947:Glucose; D011345:Fenofibrate