UW–Madison researchers have uncovered a possible way to protect key cells in the pancreas that are targeted during the development of Type 1 diabetes. A study led by Feyza Engin, a professor in the Department of Biomolecular Chemistry, showed that deleting a single stress-response gene in insulin-producing cells protects mice that are genetically predisposed to Type 1 diabetes from developing the disease.
Type 1 diabetes occurs when immune cells destroy pancreatic beta cells, leaving the body unable to produce enough insulin to regulate blood sugar. To date, most treatments have focused on preventing the immune attack. For this study, researchers focused on the beta cells themselves, investigating why they are specifically targeted.
Building on Engin’s previous work showing that deleting a stress sensor called Ire1α prevented diabetes in mice, researchers deleted the Xbp1 gene, a related stress sensor, in beta cells. Although the mice initially showed elevated blood glucose, they later returned to normal glucose levels and remained healthy for as long as a year.
Analysis revealed that beta cells lacking the Xbp1 gene temporarily lost features marking them as mature insulin-producing cells. This meant immune cells were less likely to recognize and attack them.
Next the team compared beta cells lacking Xbp1 with those missing Ire1α under identical environmental conditions, which is an important consideration for Type 1 diabetes research because environmental conditions like housing and diet can affect disease rates in mice. Using single-cell sequencing from these mouse models and gene regulatory network analysis performed by UW–Madison collaborator Sushmita Roy’s lab, the team found previously undiscovered, unique gene regulatory networks specific to Xbp1.
The findings add to evidence that beta cells play an active role in Type 1 diabetes rather than serving as passive targets. Researchers hope this information could help develop a way to identify people at high risk for Type 1 diabetes years before symptoms appear, for example by using blood tests to screen for risk biomarkers.
