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Like human cells, pancreatic cells also have a limit to how much stress they can withstand before they rupture. Through excessive stimulation of these cells, certain stresses such as inflammation and hyperglycemia cause the onset of type 2 diabetes.
As it turns out, pancreatic cell stress tolerance to two different types of molecular stress is related to DNA sequence variations that are known to increase a person’s risk of diabetes. These findings were made by researchers at The Jackson Laboratory (JAX). Stress and inflammation may increase the risk of failure or death of insulin-producing cells in individuals with genetic mutations in the pancreas.
“Ultimately we want to develop new ways to prevent and treat type 2 diabetes by targeting genes and pathways in those who are most vulnerable to this disease,” said Michael L. Stitzel, MD, an associate professor at JAX and co-senior author. Are.” The new study, with J.X. Professor Dugue Ucar, is published in the October 8 Advanced Online issue of Cell Metabolism. “These findings give us new information about some of those genes and pathways.”
The work points to dozens of genes that link cell stress and diabetes risk, including one gene already under investigation as a drug target for type 2 diabetes complications.
When living cells encounter challenges, including damage, inflammation, or changes in nutrients, they activate protective responses to cope with and overcome the stress. But over time, constant stress can overwhelm cells, causing them to slow down or die.
In pancreatic islet beta cells, two types of cell stress have previously been implicated in the development of type 2 diabetes.
In both cases, stress can eventually cause islet beta cells to stop producing insulin or die.
Stitzel and colleagues wanted to know which genes and proteins were used by islet cells to respond to both ER stress and cytokine stress.
“Researchers have completed several studies to see which molecular pathways are important in regulating insulin production in happy, healthy islet cells,” Stitzel said. “But we were working on the hypothesis that islet cells are not always happy. So which pathways are important when the cells are under stress, and how do the diabetes-associated DNA sequence changes in each of us affect them? Are?”
Stitzel’s group exposed healthy human islet cells to chemical compounds that induce ER stress or cytokine stress. Then, they tracked changes in the levels of RNA molecules in the cells, as well as how tightly or loosely different stretches of DNA were packed inside the cells – which genes and regulatory elements were expressed by the cells at any given time. A proxy for what is being used.
To analyze the results, the team collaborated with Ucar, a JAX professor and computational biologist. Together, the scientists found that more than 5,000 genes, or about a third of all genes expressed by healthy islet cells, change their expression in response to ER stress or cytokine stress. Many were involved in the production of the protein, which is important for the insulin-producing role of islet cells. And most genes were involved in only one or the other stress response, leading to the idea that two different stress pathways play a role in diabetes.
In addition, one of the eight regulatory regions of DNA commonly used in islet cells was altered due to stress. Importantly, 86 of these regulatory regions were found to have genetic variants in people already at risk for type 2 diabetes.
“This suggests that people with these genetic variants may have islet cells that respond worse to stress than other people,” Stitzel said. “Your environment — things like diabetes and obesity — pulls the trigger for type 2 diabetes, but your genetics load the gun.”
Stitzel hopes the new list of regulatory regions and genes will eventually lead to new drugs to prevent or treat diabetes by making islet cells more resilient to stress.
The researchers discovered one gene that was changed due to both ER stress. This gene, called MAP3K5, was shown to alter islet beta cell death in mice with diabetes-causing mutations in the insulin-encoding gene.
In the new paper, Stitzel and colleagues showed that higher levels of MAP3K5 caused more islet beta cells to die in response to ER stress. On the other hand, by deleting or blocking MAP3K5, islet cells became more resilient to ER stress and were less likely to die.
Early studies of selonsertib, a drug that targets MAP3K5, have shown that it may reduce the risk of serious complications of diabetes. The new results point to another potential role for the drug – in the prevention of diabetes in people at highest risk of the disease, by helping their islet cells function and survive despite cellular stress.
“It’s really exciting that this therapeutic is already in clinical trials, but a lot more work is needed to understand whether the drug can be leveraged in primary prevention,” Stitzel said .
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