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10:03
A Zebrafish Model of Diabetes Mellitus and Metabolic Memory
Published on: February 28, 2013
Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent
Assam El-Osta1, Daniella Brasacchio, Dachun Yao
1Diabetes 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
The Journal of Experimental Medicine
|September 24, 2008
Summary
Short spikes in high blood sugar (hyperglycemia) can cause lasting epigenetic changes in blood vessel cells, independent of average blood sugar levels (HbA1c). These changes may increase the risk of diabetic complications.
Area of Science:
- Endocrinology
- Molecular Biology
- Vascular Biology
Background:
- Diabetes management aims to lower HbA1c to prevent complications, but HbA1c explains less than 25% of complication risk.
- Glycemic variability and transient hyperglycemia spikes are potential risk factors not fully captured by HbA1c.
Purpose of the Study:
- To investigate if transient hyperglycemia spikes cause long-lasting epigenetic changes in vascular cells.
- To determine if these changes are independent of mean glycemia (HbA1c) and contribute to diabetic complications.
Main Methods:
- Exposing aortic endothelial cells in vitro and in vivo to transient hyperglycemia.
- Analyzing epigenetic modifications, gene expression (p65, MCP-1, VCAM-1), and the role of mitochondrial superoxide and alpha-oxoaldehydes.
Main Results:
- Transient hyperglycemia induced persistent activating epigenetic changes at the NF-kappaB p65 promoter in endothelial cells.
- These epigenetic changes and increased p65 gene expression lasted for at least 6 days after normal glycemia was restored.
- NF-kappaB-driven increases in MCP-1 and VCAM-1 expression also persisted.
- Reducing mitochondrial superoxide or alpha-oxoaldehydes prevented hyperglycemia-induced epigenetic and gene expression changes.
Conclusions:
- Short-term hyperglycemic spikes induce durable, activating epigenetic alterations in vascular cells.
- These lasting changes, mediated by NF-kappaB, may represent an HbA1c-independent risk factor for diabetic vascular complications.
- Targeting mitochondrial superoxide and alpha-oxoaldehydes could mitigate hyperglycemia's long-term vascular effects.
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