Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

J Exp Med. 2008 Sep 29;205(10):2409-17. doi: 10.1084/jem.20081188. Epub 2008 Sep 22.

Abstract

The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c-independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor kappaB (NF-kappaB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-kappaB-induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced alpha-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c-independent risk factor for diabetic complications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Cattle
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Diabetes Complications
  • Diabetes Mellitus / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology
  • Epigenesis, Genetic*
  • Gene Expression Regulation*
  • Glucose / metabolism*
  • Glycated Hemoglobin A / genetics
  • Glycated Hemoglobin A / metabolism
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Hyperglycemia / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Promoter Regions, Genetic
  • Protein Methyltransferases
  • Reactive Oxygen Species / metabolism
  • Risk Factors
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Uncoupling Protein 1
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Blood Glucose
  • CCL2 protein, human
  • Chemokine CCL2
  • Glycated Hemoglobin A
  • Ion Channels
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Transcription Factor RelA
  • Uncoupling Protein 1
  • Vascular Cell Adhesion Molecule-1
  • hemoglobin A1c protein, human
  • Superoxide Dismutase
  • Histone Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Glucose