Epigenetic mapping shows how blood sugar-regulating cells change in T2DM

Single-cell epigenetic analysis has revealed how DNA methylation reshapes insulin and glucagon regulation in pancreatic cells, with findings that clarify mechanisms of beta cell dysfunction in type 2 diabetes and point towards targeted therapeutic strategies

Researchers at Lund University, Sweden, have delivered the most detailed characterisation to date of the epigenome in pancreatic cells that regulate blood glucose, with findings that have clarified how chemical modifications to DNA influence both insulin-producing beta cells and glucagon-producing alpha cells. The study has also identified how these regulatory patterns shift in type 2 diabetes (T2DM), offering a more precise molecular framework for the disease.

All human cells contain an identical genetic code, yet distinct cell types arise through selective activation or repression of genes. This regulatory layer – the epigenome – determines cellular identity and function. In the pancreas, beta cells synthesise insulin to reduce blood glucose, while alpha cells produce glucagon to increase it. 

A stable physiological balance between these hormones remains essential for metabolic homeostasis. When this balance deteriorates, sustained hyperglycaemia may follow, which increases the likelihood of progression to T2DM.

To interrogate this process at high resolution, the research team analysed hundreds of thousands of pancreatic cells obtained from 24 individuals, including both healthy participants and those with T2DM. This approach enabled the team to construct a comprehensive map of epigenetic regulation at single-cell level, with a particular focus on DNA methylation, a mechanism in which small chemical groups attach to DNA to modulate gene activity without alteration to the underlying sequence. The resulting dataset has revealed how epigenetic landscapes differ not only between cell types but also between healthy and diseased states.

“It has made it possible, for the first time, to describe detailed, cell-specific epigenetic patterns. The study shows that many genes central to insulin and glucagon production are regulated by differences in DNA methylation,” said Dr. Charlotte Ling, professor of epigenetics at Lund and lead author of the study.

To move beyond descriptive mapping, the researchers then investigated whether targeted manipulation of DNA methylation could alter gene activity within insulin-producing cells. In controlled experiments using cultured beta cells, they modified methylation patterns in genomic regions associated with insulin and glucagon regulation. These interventions demonstrated that epigenetic editing can directly influence hormone-related gene expression which has provided proof of principle that such mechanisms may serve as therapeutic entry points.

“Here, for the first time, we show exactly which regions regulate insulin and glucagon production through DNA methylation, which gives us the opportunity to develop future treatments based on epigenetics,” said Ling.

A particularly notable discovery concerned the transcription factor ONECUT2, a regulatory protein that governs gene expression levels within cells. The study found that ONECUT2 exhibited elevated epigenetic activity in beta cells derived from individuals with T2DM. This increase was associated with impaired mitochondrial energy production and reduced insulin secretion capacity, both of which are hallmark features of beta cell dysfunction in the disease. The findings have suggested a mechanistic link between altered epigenetic regulation and the progressive decline in beta cell performance.

“This gives us a deeper understanding of why beta cells lose their function in diabetes. In the longer term, this knowledge could help us identify more personalised treatment targets,” Ling said.

The implications of this work extend beyond descriptive biology into potential clinical application. If researchers can identify which epigenetic modifications remain reversible, it may become possible to design interventions that restore functional capacity in pancreatic cells affected by diabetes. Such strategies would represent a shift towards precision medicine, in which therapies target specific molecular defects within defined cell populations.

“We now want to understand which of these changes can actually be reversed, and whether this can help beta cells regain their function in diabetes. A key aspect is to see whether the effects of editing DNA methylation can be sustained in the cell over time,” Ling added.

The study has therefore established a detailed reference framework for the epigenetic regulation of glucose homeostasis while also highlighting molecular targets that may underpin future therapeutic development.

For further reading please visit: 10.1038/s42255-026-01498-9