Relieving stress in insulin-producing cells protects against type 1 diabetes

Removing a gene that manages stress within insulin-producing beta cells draws helpful attention from the immune system, protecting mice predisposed to type 1 diabetes from developing the disease, a new University of Wisconsin–Madison study shows. The study also found that changes discovered in the modified mouse beta cells are present in human beta cells that manage to survive the widespread beta-cell death that characterizes type 1 diabetes. This gives the researchers hope that their findings, published in the journal Cell Metabolism, may point to a potential new treatment that could be administered very early in the development of diabetes. 

The endoplasmic reticulum is like the cell’s warehouse staff. It folds the insulin protein molecules that a beta cell produces, packing them for shipping to other parts of the body. If something goes wrong with the protein folding process, the shipping process backs up or even stops, stressing the endoplasmic reticulum. A stress-response gene called Atf6 perks up when a cell is struggling with unfolded proteins. But if Atf6 can’t resolve the protein-folding problem, prolonged stress will eventually kill the cell.

Feyza Engin, a UW–Madison professor of biomolecular chemistry, and colleagues bred a line of diabetes-predisposed mice without the Atf6 gene in their beta cells. Instead of meeting their typical fate, those mice were protected from diabetes. Analysis of the genes expressed by their beta cells suggested the cells entered a state called senescence far ahead of schedule. (Senescence is a period of the cell’s life cycle in which it stops dividing and halts other normal cellular business.) Engin says, “Instead of dying off, these cells unexpectedly appear to go into an early senescence state that initiated a beneficial immune response and helped the cells survive an autoimmune attack.”

Even more exciting, Engin says, is how closely the new study’s results in mice appear to be reflected in human cells. While nearly all beta cells die off in type 1 diabetes, a few—though too few to be effective insulin suppliers—do survive. To see whether their mouse findings could be applicable in humans, Engin’s lab, with collaborators at Case Western Reserve University, Université Libre de Bruxelle and the University of Manitoba, studied beta cell samples taken from type 1 diabetes patients. “In those surviving beta cells, we found reduced Atf6 activity and an early senescence gene expression pattern, suggesting this same process that kept our mice from becoming diabetic may have worked to protect these residual beta cells in humans,” Engin says. The researchers hope to build on these findings by delving further into the role and potential benefits of senescence in type 1 diabetes and other diseases.

Source: Chris Barncard, Medical Xpress, November 10, 2023; see source article