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

By A. El-Osta, D. Brasacchio, Dachun Yao, A. Pocai, P. Jones, R. Roeder, M. Cooper, M. Brownlee. Journal of Experimental Medicine, 2008

1,076 citations recorded by the source corpus.

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 κB (NF-κB) 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-κB–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 α-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.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9468d4321aa1f7ec62aa9ceb5f1324ee1e106785

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. J. Forbes
2. Leif Groop
3. C. Ling
4. Qingzheng Kang
5. M. Cooper
6. Chunxue Yang

Citations in the corpus

• The Diabetes Mellitus–Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation (2020, background): “Thus, cytokines, chemokines, and adhesion molecules are affected by hyperglycemia through the regulation of one of the crucial pro-inflammatory transcription factors related to vascular and metabolic complications, among which is atherosclerosis [80].”
• Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications (2020, background): “and in vivo, which gives rise to enhanced transcription of p65 [114], and the increased NF-κB augments the apoptosis of retinal cells in diabetes.”
• International Consensus on Use of Continuous Glucose Monitoring (2017, background): “• Benefits of rtCGM use have also been reported in individuals with T2D who are managed with or without intensive insulin treatment (44-46) [B,C,C].”
• Child health, developmental plasticity, and epigenetic programming. (2011, neutral): “(373) reported that the epigenetic and gene”
• Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes (2009, background): “Moreover, because the time-averaged mean levels of glycemia, measured as A1C, only explain part of the variation in risk of developing diabetic complications, it was recently hypothesized that transient exposures to hyperglycemia may induce sustained epigenetic changes and thereby NF- B– regulated g”
• Molecular mechanisms of diabetic kidney disease. (2014, neutral): “Persistent and excessive NFκB activation is likely further exacerbated by epigenetic changes (53).”
• Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes – Mechanisms, Management, and Clinical Considerations (2016, neutral): “High glucose concentrations lead to macrophage inflammation and enhancement of response to inflammation,(58) and even transient hyperglycemia leads to epigenetic changes with activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway that persists even after return ”
• Mechanisms of diabetic complications. (2013, background): “In experimental models of diabetes, a similar metabolic memory phenomenon has been observed in cell culture (168) and in animal models where restoration of glycemic control at specific time points using islet transplantation was unable to prevent retinopathy (85, 169, 311).”
• The Role of Oxidative Stress and Antioxidants in Diabetic Wound Healing (2021, background): “Hyperglycemia or short-term glucose fluctuations induced OS and proatherogenic gene expression alteration which will be long-lasting later even in normal glycemic conditions [67].”