Unveiling the Link Between Genetics, Stress, and Type 2 Diabetes

The cells in the human pancreas have a limit to how much stress they can withstand before degenerating. Overtaxing these cells, some stressors, including inflammation and elevated blood sugar, play a role in the onset of type 2 diabetes.

Researchers at The Jackson Laboratory (JAX) have discovered that DNA sequence variations, known to increase an individual's risk for diabetes, are associated with how effectively pancreatic cells can manage two distinct types of molecular stress.

Individuals who have these genetic alterations may be more susceptible to stress and inflammation-induced failure or death of the pancreatic cells that produce insulin.

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

Michael L. Stitzel, Associate Professor and Co-Senior Author, The Jackson Laboratory

The study was published in the journal Cell Metabolism.

The research identifies dozens of genes, one of which is presently being studied as a potential therapeutic target for type 2 diabetes problems, that link cell stress and diabetes risk.

Cells Under Stress

Living cells initiate defensive responses in an attempt to manage and reverse stress when they encounter obstacles such as damage, inflammation, or nutritional changes. However, persistent stress can eventually overwhelm the cells, slowing or killing them.

Type 2 diabetes has previously been linked to two different forms of cell stress in the islet beta cells of the pancreas.

• Endoplasmic reticulum (ER) stress occurs when the cells get overloaded with a strong need to create proteins like insulin to assist regulate blood sugar levels.
• When the immune system produces too many inflammatory signals, as it might in obesity and metabolic diseases, cytokine stress results.

Stress can eventually cause islet beta cells to stop releasing insulin or to disappear in both situations.

To understand how islet cells respond to cytokine and ER stress, Stitzel and his colleagues sought to identify the genes and proteins involved.

Researchers have completed multiple studies looking at what molecular pathways are important in regulating insulin production in happy, healthy islet cells. But we were working on this 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?”

Michael L. Stitzel, Associate Professor and Co-Senior Author, The Jackson Laboratory

Stress-Response Genes

Stitzel's team subjected human islet cells in good health to chemicals that are known to cause cytokine stress or endoplasmic reticulum stress.

Next, they monitored alterations in the RNA molecule concentrations within the cells, as well as the degree of packing of distinct DNA segments, which serve as a surrogate for the genes and regulatory segments that the cells are utilizing at that particular moment.

The researchers worked with Ucar, a Professor and Computational Biologist at JAX, to examine the data. In response to ER stress or cytokine stress, scientists discovered that over 5,000 genes, or over a third of all the genes expressed by healthy islet cells, alter in expression.

A large number were engaged in the synthesis of proteins, which is essential for the function of islet cells in making insulin. Furthermore, the majority of the genes were only implicated in one type of stress response, suggesting that diabetes may be caused by two different stress pathways.

Stress modified about one out of every eight regulatory regions of DNA that are normally utilized by islet cells. Significantly, it was previously discovered that those most at risk of type 2 diabetes carried genetic variations in 86 of these regulatory areas.

What this suggests is that people with these genetic variants may have islet cells that respond worse to stress than other people. Your environment – things like diabetes and obesity pull the trigger with type 2 diabetes, but your genetics load the gun.”

Michael L. Stitzel, Associate Professor and Co-Senior Author, The Jackson Laboratory

Stitzel thinks that by perhaps increasing the stress tolerance of islet cells, the new list of regulatory areas and genes can eventually lead to novel medications to cure or prevent diabetes.

A Druggable Target

One gene that has been impacted by both ER stress was identified by the researchers. The gene known as MAP3K5 has been demonstrated to modify islet beta cell death in mice with an insulin-encoding gene mutation that causes diabetes.

Stitzel and colleagues demonstrated in the recent work that increased MAP3K5 levels were associated with an increased rate of islet beta cell death in response to ER stress. Conversely, the islet cells became less prone to perish and more resistant to ER stress when MAP3K5 was eliminated or blocked.

Early research on the medication Selonsertib, which targets MAP3K5, suggested that it may lower the risk of serious diabetes complications. The latest results suggest another prospective purpose of the drug in the prevention of diabetes in patients most at risk of the condition, to help their islet cells continue active and alive in the face of cellular stress.

“It is really exciting that this therapeutic is already in clinical trials but much more work is needed to understand whether the drug might be able to be leveraged in primary prevention,” said Stitzel.