Researchers have recently found that genetic variations linked to a higher risk of diabetes relate to how effectively pancreatic cells manage two types of molecular stress. Individuals with these genetic variations may experience a greater likelihood of insulin-producing cells in the pancreas failing or dying under stress and inflammation.
Similar to individuals, pancreatic cells can endure a limited amount of stress before they begin to deteriorate. Conditions such as inflammation and elevated blood sugar levels contribute to the onset of type 2 diabetes by overwhelming these cells.
Scientists at The Jackson Laboratory (JAX) have identified that genetic changes associated with an increased diabetes risk are connected to the capacity of pancreatic cells to manage two distinct forms of molecular stress. In those possessing these genetic variations, the cells responsible for producing insulin in the pancreas may fail more frequently or die when faced with stress and inflammation.
“Our ultimate goal is to find innovative ways to prevent and treat type 2 diabetes by focusing on the genes and pathways that are disrupted in those most susceptible to the disease,” stated Michael L. Stitzel, an associate professor at JAX and co-senior author of the study alongside JAX professor Dugyu Ucar, which was published on October 8 in the advanced online edition of Cell Metabolism. “This research provides valuable insights into some of those genes and pathways.”
The findings highlight numerous genes that link cellular stress to diabetes risk, including one currently being studied as a drug target for complications related to type 2 diabetes.
Cellular Stress Response
When living cells face challenges such as damage, inflammation, or changes in nutrients, they activate protective mechanisms to cope with and rectify the stress. However, prolonged stress can eventually overwhelm the cells, resulting in a slowdown in function or cell death.
Specifically, in the islet beta cells of the pancreas, two forms of cellular stress have previously been identified as contributing factors in the development of type 2 diabetes.
- Endoplasmic reticulum (ER) stress happens when there is excessive demand on cells to produce proteins, such as insulin, which helps regulate blood sugar levels.
- Cytokine stress arises when the immune system sends out excessive inflammatory signals, a situation often associated with obesity and metabolic diseases.
In both instances, stress can inhibit the ability of islet beta cells to produce insulin or lead to their death.
Stitzel and his colleagues were interested in the genes and proteins that islet cells utilize to respond to both ER stress and cytokine stress.
“Many researchers have conducted studies to identify the molecular pathways pertinent to insulin production in healthy islet cells,” Stitzel noted. “However, we hypothesized that islet cells are not always functioning optimally. Thus, we aimed to discover which pathways are essential when the cells are under stress, and how genetic variations linked to diabetes affect them.”
Genes Involved in Stress Response
Stitzel’s team subjected healthy human islet cells to chemical compounds that induce either ER stress or cytokine stress. They then monitored changes in RNA levels within the cells and assessed the compaction of various DNA segments within the cells—indicators of which genes and regulatory elements are active at any given moment.
To interpret the findings, the team collaborated with Ucar, a professor and computational biologist at JAX. Together, they discovered that over 5,000 genes—about a third of all genes expressed by healthy islet cells—alter their expression in reaction to either ER stress or cytokine stress. Many of these genes are involved in protein production, essential for the insulin-producing function of islet cells. Furthermore, most genes appeared to respond exclusively to one type of stress, suggesting the existence of two distinct stress pathways in relation to diabetes.
Additionally, approximately one in eight regulatory DNA regions typically utilized in islet cells were affected by stress. Notably, 86 of these regions have previously been identified as containing genetic variants in individuals most at risk for type 2 diabetes.
“This implies that individuals with these genetic variations might have islet cells that respond less effectively to stress,” Stitzel remarked. “While environmental factors like diabetes and obesity can trigger the onset of type 2 diabetes, genetic factors create the predisposition.”
Stitzel hopes that the insights regarding the new list of genes and regulatory regions may ultimately contribute to the development of therapies designed to enhance the resilience of islet cells against stress, thereby preventing or treating diabetes.
A Potential Drug Target
The researchers concentrated on one gene altered by both ER stress—MAP3K5—which has been shown to affect islet beta cell death in mice with a gene mutation leading to diabetes.
In their recent study, Stitzel and his team revealed that higher levels of MAP3K5 resulted in an increased death rate of islet beta cells in response to ER stress. Conversely, removing or inhibiting MAP3K5 made islet cells more resistant to ER stress, thus reducing cell death risk.
Initial trials of Selonsertib—a drug targeting MAP3K5—suggest that it may lower the chances of severe complications associated with diabetes. The current findings indicate another potential use for the drug: to help prevent diabetes in high-risk individuals by ensuring their islet cells remain functional under stress.
“It’s incredibly exciting that this therapy is already undergoing clinical testing; however, further research is needed to determine if this drug could be effective for primary prevention,” Stitzel concluded.
