Long-Term Impact of Cumulative Hyperglycaemia on DNA Methylation and its Role in Diabetic Kidney Disease

Hyperglycaemia is a hallmark of diabetes and a major risk factor for diabetic kidney disease (DKD). However, the molecular consequences of long-term cumulative hyperglycaemia (CH) remain unclear. As a stable epigenetic modification, DNA methylation may capture past glycaemic exposure. Here, we assessed CH-associated DNA methylation in 1,245 participants with type 1 diabetes (T1D) from Finland and the United Kingdom-Republic of Ireland cohorts. We identified 17 CH-associated CpGs, with the strongest association at cg19693031 (TXNIP). Longitudinal analyses demonstrate that these CH-associated DNA methylation levels remain stable despite short-term glycaemic fluctuations, suggesting lasting epigenetic imprints of earlier metabolic control. Integrative analyses combining genomic, epigenetic, and proteomic data characterized these CpGs and potential target proteins. Mendelian randomization suggested a causal association between cg20853880 (KLF11) and DKD, supported by chromatin accessibility and kidney KLF11 expression. Our findings suggest that epigenetic changes contribute to metabolic memory and may mediate the effects of hyperglycaemia on DKD.