Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine–guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68–97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.

糖尿病控制和并发症试验（DCCT）和糖尿病干预与并发症流行病学（EDIC）随访中观察到了代谢记忆，即早期血糖控制对预防和/或延迟糖尿病并发症发展的持续益处。研究，但其潜在机制仍不清楚。在这里，我们通过检查表型遗传的甲基化（DNAme）与先前的血糖史以及随后的18年期并发症在499名1型DCCT参与者血液DNA中的并发症的发展之间的关系，显示了表观遗传DNA甲基化（DNAme）参与了代谢记忆。糖尿病患者也接受EDIC随访。我们证明了DCCT结束附近的DNAme与DCCT期间的平均HbA1c（平均DCCT HbA1c）之间有186个胞嘧啶-鸟嘌呤二核苷酸（CpGs）之间的关联（FDR <15％，其中FDR <5％时为43）。位于与并发症相关的基因中。对生物学功能的探索研究表明，这些CpGs富含C / EBP转录因子的结合位点，以及血细胞和造血干细胞中的增强子/转录区，以及髓样细胞中的开放染色质状态。中介分析显示，值得注意的是，几种CpG的组合解释了平均DCCT HbA1c与EDIC并发症风险之间的关系的68–97％。总之，关键CpG的DNAme似乎介导了高血糖症与代谢记忆并发症之间的联系，