Long-Term Impact of Cumulative Hyperglycaemia on DNA Methylation and its Role in Diabetic Kidney Disease
- 1Folkhalsan Research Center. Department of Nephrology, University of Helsinki and Helsinki University Hospital. Research Program for Clinical and Molecular Metab
Abstract
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.
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BibTeX
@misc{luo2026longterm,
title = {{Long-Term Impact of Cumulative Hyperglycaemia on DNA Methylation and its Role in Diabetic Kidney Disease}},
author = {X. Luo and A. Syreeni and C. Hill and L. J. Smyth and E. H. Dahlstrom and S. Mutter and Z. Chen and R. Natarajan and S. Pan and A. Parton and H. Jackson and G. McKay and K. Susztak and J. N. Hirschhorn and J. C. Florez and A. P. Maxwell and P.-H. Groop and A. J. McKnight and N. Sandholm},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361614},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361614v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Long-Term Impact of Cumulative Hyperglycaemia on DNA Methylation and its Role in Diabetic Kidney Disease
AU - X. Luo
AU - A. Syreeni
AU - C. Hill
AU - L. J. Smyth
AU - E. H. Dahlstrom
AU - S. Mutter
AU - Z. Chen
AU - R. Natarajan
AU - S. Pan
AU - A. Parton
AU - H. Jackson
AU - G. McKay
AU - K. Susztak
AU - J. N. Hirschhorn
AU - J. C. Florez
AU - A. P. Maxwell
AU - P.-H. Groop
AU - A. J. McKnight
AU - N. Sandholm
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361614
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361614v1
AB - 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.
ER -