Study Links Type 1 Diabetes Genetic Risk to Brain Cells

Type 1 diabetes is an autoimmune condition in which the body’s immune system attacks its own insulin-producing cells in the pancreas. Most studies have focused on pathogenic immune responses, but clinical and experimental observations suggest that regions outside immune response genes, including those related to neurologic function, may affect disease progression.

Now, a study published recently in Nature Communications suggests that some of these relationships may reflect shared genes that affect brain function.

“There are shared genes from neurologic function and type 1 diabetes,” says senior author David A. Alagpulinsa, PhD, assistant professor of comparative medicine at Yale School of Medicine. “Our findings suggest that genetic mechanisms regulating biological processes in brain-resident cells are shared with those regulating immune cell function relevant to type 1 diabetes.”

Although environmental factors play a major role, genetic variation contributes to both type 1 diabetes and cognitive traits. Alagpulinsa was interested in whether their genetic underpinnings overlap.

A number of observational studies have identified impairments in several measures of brain function in patients with type 1 diabetes but the relationship between these findings, the genes associated with these traits, and the development of type 1 diabetes was not understood.

“Traditionally, researchers have studied the genetic contribution to type 1 diabetes by focusing on immune cells and the pancreatic beta cells attacked by those immune cells,” Alagpulinsa says. “We took a different approach. We asked whether the genetic signals associated with type 1 diabetes are also active in brain cells.”

Using genetic signals associated with type 1 diabetes risk derived from large population cohorts, including the UK Biobank (approximately 20,000 individuals with type 1 diabetes and 500,000 people without diabetes), the researchers mapped these signals onto regulatory regions active in brain cells across developmental stages to determine where they were “switched on.”

Their findings pointed to microglia—the brain’s resident immune cells (pictured above)—as a key cell type in which these genetic signals were enriched. This pattern was consistent across all developmental stages, from fetal life to adulthood.

“One of the most important findings in our work is that genetic variation associated with type 1 diabetes is also active in brain cells,” Alagpulinsa says. “This is one of the first studies tying microglia to genetic risk associated with type 1 diabetes.”

The researchers also used a statistical approach called Mendelian randomization, which uses genetic variants from large population studies to test whether one trait influences another. The team tested whether genetic variants in modules associated with cognitive function are associated with liability for type 1 diabetes.

The researchers found no evidence that genetic liability to type 1 diabetes influences cognitive traits. Instead, genetic liability associated with certain cognitive traits was associated with differences in type 1 diabetes risk.

“Correlation is not causation,” Alagpulinsa says. “These findings do not mean that type 1 diabetes causes cognitive differences, nor do they mean cognitive traits directly cause type 1 diabetes. Rather, both may reflect shared underlying biological pathways.”

These findings support a broader, systemic view of type 1 diabetes rather than one confined to the pancreas or immune cells, says Alagpulinsa.

“Neuroimmunology is an emerging field and plays an important role in many disease conditions,” he says.

Subtle cognitive differences observed in some patients may not be solely explained by blood sugar fluctuations, but may also reflect shared underlying biology, the researchers say.

While the study maps genetic connections, it also highlights the role of environment and behavior.

“Genetic variants are like seeds,” Alagpulinsa says. “But you need soil for them to grow. The soil is the environment, your lifestyle.” While genetic variation contributes to the risk of many diseases, including type 1 diabetes, factors like education, health habits, and environment can still meaningfully shape outcomes, he says.

“Our hope is to see more researchers become interested in studying neuroimmune communication in the context of type 1 diabetes,” he says.