Pancreatic cells, like human cells, have a limit to how much stress they can handle before they start to break down. Through overstimulation of these cells, certain stresses, such as inflammation and hyperglycemia, can lead to the onset of type 2 diabetes.
Genetic Links to Stress Tolerance
Researchers at The Jackson Laboratory (JAX) have found that pancreatic cell stress tolerance to two distinct types of molecular stress is correlated with DNA sequence variations that are known to raise an individual’s risk for diabetes. Stress and inflammation may increase the risk of failure or death of the insulin-producing cells in individuals with these genetic alterations in the pancreas.
“Ultimately we want to develop new ways to prevent and treat type 2 diabetes by targeting the genes and pathways that are perturbed in people who are most susceptible to the disease,” said Michael L. Stitzel, associate professor at JAX and co-senior author of the study. “These findings give us new insight into some of those genes and pathways.”
Identifying Key Genes and Pathways
The research points toward dozens of genes that connect cell stress and diabetes risk, including one that is already under investigation as a drug target for type 2 diabetes complications. When living cells face challenges, such as damage, inflammation, or nutrient changes, they activate protective responses. However, sustained stress can overwhelm the cells, causing them to slow down or die.
In the pancreas’ islet beta cells, two types of cell stress have been implicated in the development of type 2 diabetes. In both cases, stress can lead to either a cessation of insulin production or cell death.
Investigating Cellular Responses to Stress
Stitzel and his colleagues aimed to identify which genes and proteins are involved in islet cells’ responses to both endoplasmic reticulum (ER) stress and cytokine stress.
“Researchers have completed multiple studies looking at what molecular pathways are important in regulating insulin production in happy, healthy islet cells,” Stitzel noted. “But we were working on the hypothesis that islet cells are not always happy. So what pathways are important when the cells are under stress, and how do diabetes-linked DNA sequence changes in each of us affect them?”
The team exposed healthy human islet cells to chemical compounds that induce either ER stress or cytokine stress. They tracked changes to RNA levels in the cells and examined the packing of different stretches of DNA, which serves as a proxy for gene activity.
Key Findings
Through their analysis, the researchers found that over 5,000 genes—nearly a third of all genes expressed by healthy islet cells—changed expression in response to ER or cytokine stress. Many of these genes are involved in protein production, crucial for islet cells’ insulin-producing function. Notably, most genes were specific to one stress response, suggesting that separate pathways play distinct roles in diabetes.
Additionally, around one in eight regulatory regions of DNA typically used in islet cells were altered by stress. Importantly, 86 of these regulatory regions contained genetic variants linked to an increased risk of type 2 diabetes.
“What this suggests is that people with these genetic variants may have islet cells that respond worse to stress than other people,” Stitzel explained. “Your environment—things like diabetes and obesity—pulls the trigger for type 2 diabetes, but your genetics load the gun.”
Future Directions
Stitzel hopes that the new list of regulatory regions and genes will lead to the development of new drugs that can prevent or treat diabetes by making islet cells more resilient to stress.
The research focused on a gene known as MAP3K5, which was altered by both ER stress and has been shown to influence islet beta cell death in mice with a diabetes-causing mutation. The study demonstrated that higher levels of MAP3K5 resulted in more islet beta cell death in response to ER stress. Conversely, blocking MAP3K5 made the islet cells more resilient and less likely to die.
Therapeutic Implications
Early studies of Selonsertib, a drug targeting MAP3K5, have shown it could reduce the risk of severe complications of diabetes. The new findings suggest another potential role for the drug: preventing diabetes in those most at risk, helping to keep their islet cells functional and alive amid cellular stress.
“It’s really exciting that this therapeutic is already in clinical trials, but much more work is needed to understand whether the drug might be leveraged in primary prevention,” Stitzel concluded.
(INCLUDES INPUTS FROM ANI)
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