As we get older, many people remain able to keep their blood sugar under control, even though the body often becomes less responsive to insulin. New research suggests that this is partly because pancreatic beta cells gradually adapt over time through subtle epigenetic changes, which help preserve the identity and function of these insulin-producing cells.
In Type 2 diabetes, the same process appears to happen more quickly. This may reflect an early compensatory response to ongoing metabolic stress, which eventually becomes unsustainable. The findings offer a more detailed picture of how beta cells respond to ageing and diabetes, and could help guide future efforts to protect their function.
More than half a billion people worldwide are living with diabetes, the vast majority with Type 2 diabetes (T2D), a chronic condition that is becoming more common as populations age and lifestyles change. Yet the mechanisms that drive beta-cell adaptation and failure over time have not been fully understood.
A study published in Nature Metabolism, led by Dr Dana Avrahami-Tzfati of the Hebrew University, together with Dr Elisabetta Manduchi and Prof. Klaus Kaestner of the University of Pennsylvania, has now shed new light on how the body’s insulin-producing cells change across a lifetime, and how this response is altered in Type 2 diabetes.
Pancreatic beta cells release insulin to regulate blood glucose, and they must constantly adjust to changing metabolic demands. Using cell-specific methylome data from the Human Pancreas Analysis Program, the researchers examined DNA methylation — a stable chemical mark that helps control gene activity over time — to understand how beta cells adapt.
An epigenetic pattern of ageing
In healthy individuals, the team found a gradual age-related decrease in methylation in beta cells. This change took place in important regulatory regions of the genome and appears to help maintain the activity of genes needed for insulin production over many years.
By contrast, nearby alpha cells, which produce glucagon, followed a different pattern of ageing and showed a slight increase in methylation. This difference suggests that beta cells have a particularly active role in adjusting to metabolic stress throughout life.
“We found that ageing in the pancreas is not just a process of decline, but one of constant adjustment,” said Dr Avrahami-Tzfati. “Beta cells are essentially running a marathon to keep blood sugar stable. They can do this remarkably well for decades — but in Type 2 diabetes, that marathon turns into a sprint.”
What happens in diabetes
In people with Type 2 diabetes, the researchers observed even greater loss of methylation in beta cells than in people without diabetes. This suggests that the same adaptive process seen in healthy ageing may be intensified in response to long-term metabolic stress.
At first, this stronger response may help beta cells keep insulin production going. But over time, it may become too much for the cells to sustain. As a result, beta cells gradually lose their ability to function properly, contributing to Type 2 diabetes.
This shifts the way we think about the disease. Rather than seeing Type 2 diabetes simply as a sudden failure of insulin production, the study suggests it may develop when a long-term adaptive response is pushed beyond its limits.
Why it matters
These findings are important because diabetes is a major cause of heart disease, kidney failure, blindness and early death, and it places a growing burden on individuals, families and healthcare systems.
“This study shows that mechanisms that help beta cells adapt throughout life may also be engaged more strongly under chronic stress,” said Prof. Klaus Kaestner. “Understanding this balance points to future research aimed at preserving beta-cell function and slowing disease progression.”
What this could mean for treatment
Because this adaptive process was most evident in beta cells, it may offer a useful target for future therapies. Researchers may eventually be able to explore ways to:
- reduce chronic metabolic stress on beta cells;
- preserve beta-cell identity and long-term function;
- identify when adaptation begins to turn into dysfunction.
These approaches would not replace current diabetes treatment, but they could complement it by focusing more directly on the biology of beta-cell resilience and decline.
The research paper, “Epigenetic adaptation of beta cells across lifespan and disease,” is now available in Nature Metabolism and can be accessed at https://doi.org/10.1038/s42255-026-01495-y
Researchers:
Elisabetta Manduchi, Hélène C. Descamps, Jinping Liu, Jonathan Schug, Tong Da, Deeksha Lahori, Hilana El-Mekkoussi, Michelle Lee, Eseye Feleke, Diana Bernstein, Chengyang Liu, Ali Naji, Benjamin Glaser, Klaus H. Kaestner & Dana Avrahami
Institutions:
- Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- The Human Pancreas Analysis Program (RRID:SCR_016202), Philadelphia, PA, USA.
- Department of Developmental Biology and Cancer Research, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
- Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
- Department of Surgery and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA