Many clinical studies have shown that intensive glycemic control in patients with diabetes can reduce the incidence and progression of diabetic nephropathy and can also reduce the incidence of other complications. These beneficial effects persist after patients return to usual (often worse) glycemic control. The Diabetes Control and Complications Trial was the first to refer to this phenomenon as 'metabolic memory'. Many patients with diabetes, however, still develop diabetic nephropathy despite receiving intensified glycemic control. Preliminary work in endothelial cells has shown that transient episodes of hyperglycemia can induce changes in gene expression that are dependent on modifications to histone tails (for example, methylation), and that these changes persist after return to normoglycemia. The persistence of such modifications cannot yet be fully explained, but certain epigenetic changes, as well as biochemical mechanisms such as advanced glycation, may provide new and interesting clues towards explaining the pathogenesis of this phenomenon. Further elucidation of the molecular events that enable prior glycemic control to result in end-organ protection in diabetes may lead to the development of new approaches for reducing the burden of diabetic nephropathy.
The seminal study confirming the importance of optimizing glycemic control in type 1 diabetes was the Diabetes Control and Complications Trial (DCCT) and its follow-up observational study, the Epidemiology of Diabetes Intervention and Complications (EDIC) study
Intensive glycemic control can reduce the incidence and progression of diabetic complications, including diabetic nephropathy; these benefits often persist despite a return to more usual, often worse, glycemic control
'Metabolic memory' is a term that has been used to describe the fact that prior glucose control has sustained effects that persist even after return to more usual glycemic control
Even with intensive glycemic control, some patients will still develop diabetic nephropathy and other diabetic vascular complications
Preliminary studies in vascular endothelial cells have suggested that transient hyperglycemia can influence gene expression by epigenetic mechanisms, including the methylation of particular histone tails, and that these changes persist after a return to normoglycemia
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The work of the authors is funded by grants from the Juvenile Diabetes Research Foundation (JDRF), National Health and Medical Research Council (NHMRC) and National Heart Foundation (NHF) of Australia.
The authors declare no competing financial interests.
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Tonna, S., El-Osta, A., Cooper, M. et al. Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms. Nat Rev Nephrol 6, 332–341 (2010). https://doi.org/10.1038/nrneph.2010.55
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