Type 1 diabetes occurs when immune cells attack the beta cells in the pancreas, preventing the body from producing enough insulin to regulate blood sugar levels. To date, most treatments have focused on suppressing this immune activity to prevent the attack.
Study leader Faiza Engin, a professor of molecular biochemistry at the University of Wisconsin-Madison, explained: "Historically, scientists have focused on preventing the immune attack because it is an autoimmune disease. But we looked at it from a different angle and asked: Why are beta cells specifically targeted?"
The study focused on a protein called XBP1, which is part of the cell's stress response system and helps it adapt to inflammation and the accumulation of abnormal proteins. A previous study by the Ingen lab showed that deleting a related stress sensor called Ire1α in beta cells prevents the development of diabetes in mice, and the new study builds upon this foundation.
Using a mouse model with type 1 diabetes, scientists specifically deleted the Xbp1 gene in beta cells before the immune attack began. Although blood glucose levels were initially high, the mice later returned to normal and remained healthy for up to a year.
Engin explained: "The interesting thing is that the sugar level rises initially but later returns to normal. In effect, glucose levels return from the diabetic level to the normal level."
The analysis revealed that beta cells lacking the Xbp1 gene temporarily lose their mature characteristics, reducing the likelihood of the immune system recognizing and attacking them. Over time, the cells regain their identity, inflammation decreases, and insulin production returns to normal.
Engin added: "Beta cells lose their identity and do not resemble typical cells, which is why immune cells do not recognize them."
It was remarkable that this protective effect occurred without any changes in other stress-related processes involving Ire1α, which helps to understand how different components of the cellular stress response affect disease.
To confirm these differences, the team compared beta cells lacking Xbp1 with those lacking Ire1α under the same environmental conditions, using single-cell DNA sequencing and gene regulatory network analysis. This comparison revealed shared stress response pathways and others specific to the Xbp1 gene.
The findings add to the evidence suggesting that beta cells are not just targets of disease, but play an active role in the development of type 1 diabetes.
Although the study was conducted on mice, Engin explained that the research takes into account the human disease, as people at risk of developing type 1 diabetes can be identified years before symptoms appear through blood tests.
She added: "If these individuals are identified at an early stage, can we intervene? Can the Xbp1 gene be inhibited to prevent or delay the onset of diabetes?"
The Ingen laboratory is currently continuing to study these questions, on mice and human pancreas cells grown in the lab, to explore the potential of this preventative intervention.
The study was published in the journal Nature Communications.
