Researchers at Lund University in Sweden have conducted the first study looking at epigenetic changes associated with type 2 diabetes in alpha and beta pancreatic cells. Published today in Nature Metabolism, their findings show that the ONECUT2 gene plays a key role in the development of type 2 diabetes by altering insulin production.
“The study shows that many genes central to insulin and glucagon production are regulated by differences in DNA methylation,” says Charlotte Ling, PhD, professor of epigenetics at Lund University and lead author of the study. “It has made it possible, for the first time, to describe detailed, cell-specific epigenetic patterns.”
The number of people living with diabetes is rapidly increasing worldwide, with approximately 95% of cases attributed to type 2 diabetes. This condition develops gradually and is characterized by a reduced ability to use insulin effectively, leading to elevated blood sugar levels. Over time, high blood sugar can lead to a range of complications that significantly impact the patient’s quality of life.
Lifestyle factors like diet and physical activity are major drivers of this condition; however, genetics can also contribute to the development of type 2 diabetes, increasing the risk for some people over others. While genome- and epigenome-wide studies on diabetes have identified genetic and epigenetic mechanisms involved in type 2 diabetes, previous epigenetics studies had only looked at whole tissues and none had investigated epigenetic changes within specific cell types that are involved in blood sugar regulation.
Ling’s team focused on alpha and beta pancreatic cells, which secrete insulin and glucagon hormones, respectively, to regulate blood sugar levels. By analyzing hundreds of thousands of cells from 24 people, with and without diabetes, the researchers created the most detailed epigenetics mapping of pancreatic cells to date. This allowed them to discover over 22,000 regions in nearly 8,000 genes that were differentially methylated between alpha and beta cells.
“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,” says Ling.
They then used CRISPR epigenetic editing to alter DNA methylation around the genes encoding for insulin and glucagon, which revealed that levels of the ONECUT2 transcription factor were elevated in beta cells from type 2 diabetes patients. This epigenetic upregulation was found to impair the ability of beta cells to release insulin, which in turn disrupted glucose regulation and reduced energy production within the cell.
Based on their findings, the researchers developed a web tool intended as a comprehensive resource available to researchers investigating the impact of age, sex, and type 2 diabetes on DNA methylation and gene expression in alpha and beta cells.
“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,” says Ling. “A key aspect is to see whether the effects of editing DNA methylation can be sustained in the cell over time.”
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