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Epigenetic phenomena linked to diabetic complications

Abstract

Diabetes mellitus (type 1 and type 2) and the complications associated with this condition are an urgent public health problem, as the incidence of diabetes mellitus is steadily increasing. Environmental factors, such as diet and exposure to hyperglycemia, contribute to the etiology of diabetes mellitus and its associated microvascular and macrovascular complications. These vascular complications are the main cause of the morbidity and mortality burden of diabetes mellitus. The DCCT–EDIC and UKPDS epidemiological studies correlated poor glycemic control with the development of vascular complications in patients with type 1 or type 2 diabetes mellitus. The findings of these studies suggest that early exposure to hyperglycemia predisposes individuals to the development of diabetic complications, a phenomenon referred to as metabolic memory or the legacy effect. The first experimental evidence for metabolic memory was reported >20 years ago and the underlying molecular mechanisms are currently being characterized. Interestingly, transient exposure to hyperglycemia results in long-lasting epigenetic modifications that lead to changes in chromatin structure and gene expression, which mediate these persistent metabolic characteristics.

Key Points

  • In patients with type 1 or type 2 diabetes mellitus, the clinical complications underlying morbidity and mortality have a microvascular or macrovascular nature

  • Vascular complications in patients with diabetes mellitus are primarily, although not solely, caused by hyperglycemia

  • The results of prospective, large-scale clinical trials suggest that diabetic complications attributable to poorly controlled glycemia can manifest long after initiation of an improved glycemic control regimen

  • Studies in animal models and cell cultures have demonstrated that clinical and biological responses to exposure to hyperglycemia persist even after return to normoglycemic conditions

  • In endothelial cells, hyperglycemia induces generation of reactive oxygen species and activates both the exosamine pathway and protein kinase C; these events upregulate transcription of proinflammatory mediators

  • In patients with diabetes mellitus, hyperglycemia induces long-lasting, post-translational modifications in histones that contribute (after return to normoglycemia) to the sustained expression of proinflammatory mediators involved in vascular dysfunction

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Figure 1: The DCCT–EDIC study demonstrates that a predisposition to develop diabetic complications is maintained long after switching from a poor glycemic control to a tight glycemic control regimen.
Figure 2: Histone H3 post-transcriptional alterations induced by hyperglycemia and diabetes mellitus.
Figure 3: Histone H3 and H4 post-transcriptional modifications in monocytes from control patients and patients with diabetes mellitus.
Figure 4: Dynamic exchange of coregulatory complexes and the persistence of epigenetic changes.
Figure 5: Charting genome-wide glucose-induced hyperacetylation using high-throughput massive parallel DNA sequencing coupled with chromatin immunopurification.

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Acknowledgements

We acknowledge grant and fellowship support from the Juvenile Research Diabetes Foundation, Diabetes Australia Research Trust, the National Health and Medical Research Council of Australia and the Franco-Australian INSERM-NHMRC cooperation program. A. Balcerczyk was supported by the PSF (Polish Science Foundation).

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Pirola, L., Balcerczyk, A., Okabe, J. et al. Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 6, 665–675 (2010). https://doi.org/10.1038/nrendo.2010.188

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