Newly discovered by researchers at The Jackson Laboratory (JAX), the DNA sequence changes that increase a person’s risk for developing diabetes are also associated with how well pancreatic cells respond to two types of molecular stress.
People with these DNA changes may be more likely for the insulin-producing cells of the pancreas to fail or die when this is called stress and inflammation.
“These findings provide us with new insight into some of those genes and pathways.”
This work points to dozens of genes that connect cell stress to diabetes risk, and one of them — already in the running to be a drug target for diabetes complications — is also consulted.
Cells under stress
Cells living in the body can activate protective responses when facing problems, including damage, inflammation, or changes in nutrient availability for example, in order to try to cope with and reverse the stress.
Two types of cell stress in the human pancreas’ islet beta cells have previously been linked to developing type 2 diabetes.
In both cases, the stress can eventually drive the loss of islet beta cell ability to produce insulin or their death.
Islet cells use certain genes and proteins to respond to both ER stress and to cytokine stress, Stitzel and his colleagues wanted to know what those were.
Stress-response genes
The group of Stitzel exposed chemical compounds that cause either ER stress or cytokine stress to healthy human islet cells. They then followed changes to what levels of RNA molecules there were in the cells, and how tightly, or loosely, different regions of DNA were packaged inside the cell—which represents a proxy of what genes and regulatory elements the cells are using at any moments in time.
The new list of regulatory regions and genes that Stitzel hopes will lead to new drugs to alleviate or treat diabetes may ultimately make islet cells more stress resistant, he said.
Early studies of Selonsertib, a drug that inhibits MAP3K5, have suggested that it may reduce the risk of diabetes’s serious complications. The new results open another possibility for the drug: preventing diabetes in people particularly at risk of the disease, as a way of keeping their islet cells alive and functioning in the face of cellular stress.
Early studies of a drug, Selonsertib, that targets MAP3K5 suggested that it could lower the risk of serious complications of diabetes. The new results suggest that the drug might also have another possible use in preventing diabetes in those individuals most at risk of the disease, helping their islet cells to remain healthy and alive in the unrelenting environment of cellular stress.
Reference: Laboratory J. How diabetes risk genes make cells less resilient to stress
Medical Xpress
