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Researchers from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg find evidence for a new model underpinning “de-differentiation”. Metabolic stress and breakdown of an epigenetic barrier may cause de-differentiation. Patient data suggest a central role for impaired epigenetic control in the development of the disease.
According to the International Diabetes Federation (IDF), diabetes mellitus affects billions of people across the globe. Most patients are suffering from type 2 diabetes, which usually occurs in old age and is associated with obesity and cardiovascular problems. Faulty insulin regulation triggers the widespread disease. When blood sugar levels rise after a meal and insulin is needed quickly in high quantities, the pancreas of patients releases the hormone slowly leading to high levels of glucose in the blood.
Beta cells do not die in diabetes patients but change into a different cell type. Beta cells in patients suffering from type 2 diabetes losing their identities by undergoing de-differentiation. They lose their most specialized functions and revert to a state similar to their immediate developmental precursor, a progenitor-like endocrine cell lacking the ability to secret insulin.
The team around the epigeneticist at the Max Planck Freiburg is driven by the interest in understanding of epigenetic effects in complex diseases such as diabetes, obesity and cancer. They are called complex because they result from a complex genetic predisposition but also significant non-genetic components, often termed ‘environmental influences’. This non-genetic regulation is believed to converge upon chromatin-dependent processes.
In human cells, DNA is packaged around histone proteins to make chromatin structure. The packaging of the DNA plays a crucial role in cell type-specific gene regulation, in which genes can be either switched ‘on’ or ‘off’. Healthy and de-differentiated beta cells contain the same DNA. What makes the difference are epigenetic identity barriers that are mediated by modifications of the DNA packaging.
By profiling thousands of beta cells from non-diabetic and type-2 diabetic individuals in mice and humans the team found that two out of about 25 different types of chromatin packaging the DNA, track with beta cell dysfunction: one kind of chromatin was dysregulated specifically in diabetic individuals and another one was surprisingly up-regulated, which is normally supposed to be very silent.
In cells, if the genetic programs aren’t correctly coordinated cellular identity changes, and functional specializations fade and leads to beta cells forgetting who they are and what they are supposed to do. Researchers triggered these switches to recapitulate the human disease etiology in mice. Animals with this modification were first healthy and developed regular insulin-producing beta cells. But at around middle-age, cells de-differentiated and the animals could not control their blood sugar.
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