10 october 2024 : Pancreatic cells, like all human cells, have a limit to how much stress they can handle before starting to break down. Overstimulation from factors like inflammation and high blood sugar can trigger the onset of type 2 diabetes. Researchers at The Jackson Laboratory (JAX) discovered that the pancreas’ stress tolerance is linked to DNA sequence variations that increase diabetes risk. These genetic factors may make insulin-producing cells more susceptible to failure or death under stress.
Michael L. Stitzel, an associate professor at JAX, and Dugyu Ucar, a professor, co-led a study published in Cell Metabolism on October 8. They aim to develop new strategies to prevent and treat type 2 diabetes by targeting genes and pathways disrupted in those most vulnerable to the disease. Their research identifies several genes that connect cell stress and diabetes, with some already being explored as potential drug targets.
When cells experience stress from damage, inflammation, or nutrient fluctuations, they activate protective mechanisms to cope. However, sustained stress can overwhelm these defenses, leading to cell dysfunction or death. In the pancreas, two types of stress—endoplasmic reticulum (ER) stress and cytokine stress—are known to impair insulin production or cause beta cell death, which are key factors in the development of type 2 diabetes.
The research team exposed healthy human islet cells to compounds that induce either ER stress or cytokine stress, tracking changes in RNA levels and DNA packaging. Their findings revealed that over 5,000 genes—nearly a third of all genes in healthy islet cells—respond to these stresses. These genes play roles in protein production, crucial for insulin production in islet cells. Interestingly, many genes responded to either ER or cytokine stress but not both, suggesting that these two stress pathways separately contribute to diabetes.
Additionally, one in eight regulatory regions of DNA in islet cells was altered by stress, and 86 of these regions contained genetic variants linked to an increased risk of type 2 diabetes. This suggests that people with these variants may have islet cells that are less resilient to stress. Stitzel likened it to a gun: while environmental factors like obesity and diabetes pull the trigger, genetics load the gun.
The researchers focused on one gene, MAP3K5, which was affected by both types of stress. In mice with a diabetes-causing mutation in the insulin gene, higher levels of MAP3K5 caused more beta cell death. Blocking or eliminating MAP3K5 made islet cells more resilient to stress and less likely to die.
Early trials of a drug targeting MAP3K5, called Selonsertib, show promise in reducing diabetes complications. The new findings suggest it could also prevent diabetes by helping islet cells stay functional and survive under stress, particularly in individuals at high risk. While more research is needed, this could pave the way for new treatments to protect insulin-producing cells and reduce the risk of type 2 diabetes.