Abstract
The vascular complications of diabetes significantly impact the quality of life and mortality in diabetic patients. Extensive evidence from various human clinical trials has clearly established that a period of poor glycemic control early in the disease process carries negative consequences, such as an increase in the development and progression of vascular complications that becomes evident many years later. Importantly, intensive glycemic control established later in the disease process cannot reverse or slow down the onset or progression of diabetic vasculopathy. This has been named the glycemic memory phenomenon. Scientists have successfully modelled glycemic memory using various in vitro and in vivo systems. This review emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells. Furthermore, various epigenetic marks have been proposed to closely associate with vascular glycemic memory. In addition, we comment on the importance of endothelial progenitors and their role as endogenous vasoreparative cells that are negatively impacted by the diabetic milieu and may constitute a “carrier” of glycemic memory. Considering the potential of endothelial progenitor-based cytotherapies, future studies on their glycemic memory are warranted to develop epigenetics-based therapeutics targeting diabetic vascular complications.
Highlights
The concept of glycemic memory refers to the inexorable progression of diabetic vascular complications which is linked to uncontrolled glycemia early in the disease despite a significant follow-on period of improved glycemic control
This investigation was designed following preliminary clinical studies reporting that diabetic retinopathy progression could not be arrested but worsened with tighter glycemic control [2, 3] and established that diabetic retinopathy could be prevented in diabetic dogs only if tight glycemic control began within 2 months of diabetes onset
A report on 8-year follow-up indicated that previous intensive treatment group still benefited from a delayed progression of diabetic nephropathy [5]. 18-year follow-up on Epidemiology of Diabetes Interventions and Complications (EDIC) once more demonstrated a persistent benefit for the original intensive therapy group when compared to the conventional one on retinopathy progression [32]
Summary
The concept of glycemic memory refers to the inexorable progression of diabetic vascular complications which is linked to uncontrolled glycemia early in the disease despite a significant follow-on period of improved glycemic control. Tight glycemic control starting 2.5 years after diabetes onset did not halt diabetic retinopathy progression, and interestingly retinopathy became evident during the tight glycemic period [1] This preclinical study was clinically validated with results from the Diabetes Control and Complications Trial (DCCT) [4] and its follow-up the Epidemiology of Diabetes Interventions and Complications (EDIC) trial [5]. This review summarizes past and recent research on the role of glycemic memory in the prognosis of diabetic micro and macro vascular complications, covering from experimental in vitro models to human clinical trials. It discusses the relevance of epigenetics, with particular focus on how this might impact on endothelial progenitors as one of the cellular substrates of glycemic memory
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