Format

Send to

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

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

Author information

1
Diabetes and Metabolism Division, Baker Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia. assam.el-osta@bakeridi.edu.au

Erratum in

  • J Exp Med. 2008 Oct 27;205(11):2683.

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.

PMID:
18809715
PMCID:
PMC2556800
DOI:
10.1084/jem.20081188
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center