How diabetes risk genes make cells less resistant to stress

The cells in your pancreas, like humans, can only handle a limited amount of stress before they start to break down. Certain stressors, such as inflammation and high blood sugar, contribute to the development of type 2 diabetes by overwhelming these cells.

Researchers at The Jackson Laboratory (JAX) have discovered that DNA sequence changes known to increase diabetes risk are linked to the ability of pancreatic cells to handle two different types of molecular stress. In people with these DNA changes, insulin-producing cells in the pancreas may be more likely to fail or die when exposed to stress and inflammation.

“Ultimately, we want to develop new ways to prevent and treat type 2 diabetes by targeting disrupted genes and pathways in people most susceptible to the disease,” said Michael L. Stitzel, associate professor. at JAX and co-senior author with JAX Professor Dugyu Ucar, of the study published in the October 8 online issue of Cellular metabolism.

“These findings give us new insight into some of these genes and pathways.”

The work highlights dozens of genes that link cellular stress to diabetes risk, including one that is already being studied as a drug target for type 2 diabetes complications.

Cells under stress

When living cells face challenges, including damage, inflammation, or changes in nutrients, they activate protective responses in an attempt to cope with and reverse stress. But over time, sustained stress can overwhelm cells, causing them to slow down or die.

In pancreatic islet beta cells, two types of cellular stress have previously been implicated in the development of type 2 diabetes.

• Endoplasmic reticulum (ER) stress occurs when cells are overwhelmed by high demand to produce proteins, such as insulin, to help regulate blood sugar.
• Cytokine stress occurs when the immune system sends excessive inflammatory signals, as can occur in obesity and metabolic diseases.

In either case, stress can eventually cause islet beta cells to stop producing insulin or die.

Stitzel and his colleagues wanted to know which genes and proteins were used by islet cells to respond to both ER stress and cytokine stress.

“Researchers have performed several studies on molecular pathways important in regulating insulin production in happy, healthy islet cells,” Stitzel said. “But we were working on this hypothesis that islet cells aren’t always happy. So what pathways are important when cells are under stress, and how are diabetes-related DNA sequence changes in each of us do they affect them?”

Stress response genes

Stitzel’s group exposed healthy human islet cells to chemical compounds known to induce ER stress or cytokine stress. Then, they tracked changes in the levels of RNA molecules in the cells as well as how tight or loose different DNA sequences were inside the cells – an indicator of the genes and regulatory elements used by cells at a given time.

To analyze the results, the team collaborated with Ucar, a professor and computational biologist at JAX. Together, the scientists found that more than 5,000 genes, nearly 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 protein production, which is crucial for the insulin-producing role of islet cells. And most of the genes were only involved in one or the other stress response, raising the idea that two distinct stress pathways play a role in diabetes.

Additionally, about one in eight regulatory regions of DNA typically used in islet cells was altered by stress. Importantly, 86 of these regulatory regions contained genetic variants in people at highest risk for type 2 diabetes.

“What this suggests is that people with these genetic variants might have islet cells that respond less well to stress than others,” Stitzel said. “Your environment, like diabetes and obesity, triggers 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 potentially making islet cells more resistant to stress.

A druggable target

The researchers focused on a gene modified by both stresses. Called MAP3K5, this gene has been shown to alter islet beta cell death in mice containing a diabetes-causing mutation in the gene encoding insulin.

In this paper, Stitzel and colleagues showed that higher levels of MAP3K5 caused more islet beta cells to die in response to ER stress. In contrast, removing or blocking MAP3K5 made islet cells more resistant to ER stress and less likely to die.

Early studies of Quellesertib, a drug targeting MAP3K5, showed that it may reduce the risk of serious diabetes complications. The new results suggest another possible role for the drug: in preventing diabetes in people most at risk of the disease, to help their islet cells remain functional and alive in the face of cellular stress.

“It’s really exciting that this treatment is already in clinical trials, but there is still a lot of work to be done to understand whether the drug could be used in primary prevention,” Stitzel said.