Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Abstract

We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term followup Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.T he landmark Diabetes Control and Complications Trial (DCCT; 1983-1993 clearly showed that intensive (INT) glycemic control profoundly reduces the development and progression of microvascular complications in type 1 diabetes (T1D). The DCCT participants were subsequently followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (1994 to present), during which all subjects were advised to practice INT treatment. Surprisingly, those previously assigned to conventional (CONV) therapy continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates than the previous INT therapy group, despite nearly similar HbA1c levels during the EDIC Study (1-3). This persistence of benefit from early application of INT therapy, called "metabolic memory," is an enigma in the field of T1D: recent studies have suggested the involvement of epigenetic mechanisms (4-9).Epigenetics is the study of mostly heritable changes in gene expression and phenotype that occur without alterations in the underlying DNA sequence. Epigenetic states are affected by environmental factors, such as aberrant nutrition and metabolic states (4, 6-8, 10). DNA methylation (DNA-me; the classic epigenetic mark) and posttranslational modifications (PTMs) of histo...

Omics Biomarkers in Ophthalmology

“…60,65,66 Even if hyperglycemia is short lasting, changes in the epigenome could persist due to metabolic memory. 67,68 Three genome-wide methylation studies revealed DR-specific DNA methylation profiles, and identified the natural killer cellmediated cytotoxicity pathway as potentially involved in DR pathogenesis. [67][68][69] Interestingly, an increase in global DNA methylation levels in blood has been correlated to the severity of DR, independent of common DR risk factors.…”

“…67,68 Three genome-wide methylation studies revealed DR-specific DNA methylation profiles, and identified the natural killer cellmediated cytotoxicity pathway as potentially involved in DR pathogenesis. [67][68][69] Interestingly, an increase in global DNA methylation levels in blood has been correlated to the severity of DR, independent of common DR risk factors. 67 This suggests DNA methylation patterns as potent candidate biomarkers for DR, although these findings warrant replication in larger cohorts.…”

Complications of Acute and Chronic Hyperglycemia

“…45,46 Of interest, a recent study demonstrated that specific microRNA (i.e., miR-125b and miR-146a-5) changes can cause persistent increase in proatherogenic gene expression and explain in this way the phenomenon of metabolic memory. 47 The key role of glycemic control in modulating complication risks highlighted by the DCCT/EDIC studies was also confirmed by large studies performed in adults with T2D, such as the UKPDS, where for example intensive treatment (insulin or sulfonylurea) resulted in a 25% decrease in microvascular complications.…”

The importance of epigenetic factors for the diagnostics and treatment of type 2 diabetes mellitus

“…This hypothesis is supported by the recently published results of the study by Chen et al [33], in which the level of methylation of selected loci throughout the genome was evaluated among the participants of the EDIC study with an interval of more than 16 years. It was shown that the DNA methylation profile of study participants who were subjected to conventional therapy and who developed retinopathy or microalbuminuria differs from the DNA methylation profile of participants with intensive glycemic control.…”

“…It was shown that the DNA methylation profile of study participants who were subjected to conventional therapy and who developed retinopathy or microalbuminuria differs from the DNA methylation profile of participants with intensive glycemic control. Only in the conventionally treated group, in which adequate glycemic control was not achieved, persistent hypomethylation of the gene for thioredoxin-responsive protein (TXNIP) was found, the consequence of which may be increased expression of this protein [33].…”