Probing the genetics of islet stress and resilience in type 2 diabetes

$2.8 million Department of Defense grant will fund JAX research defining gene-environment interactions of islet resilience and type 2 diabetes

What makes some people more likely than others to develop type 2 diabetes?

In type 2 diabetes, the pancreas can’t produce enough insulin, which promotes glucose uptake from the bloodstream into the cells of our body, to overcome insulin resistance. This leads to dangerously high levels of glucose in the blood. Long-term medical complications include heart disease, stroke, diabetic retinopathy and amputation (due to poor blood circulation), and is associated with a 10-year reduction in lifespan.

“Type 2 diabetes is commonly associated with obesity and sedentary lifestyle,” says Jackson Laboratory (JAX) Assistant Professor Michael Stitzel, Ph.D.(De)coding the regulatory landscape of human pancreatic islets and other metabolic cell types health and diabetesMichael Stitzel, Ph.D., “but it is fundamentally a genetic disease in which  individuals have higher or lower baseline risk of developing type 2 diabetes due to their genetic makeup. Currently, our understanding of the genes and pathways involved in development and progression of type 2 diabetes remains incomplete.”

Type 2 diabetes is a national medical and public health crisis. The latest study by the Centers of Disease Control and Prevention estimates that 14 percent of the U.S. population — that’s one in seven Americans — have type 2 diabetes, and about a third of those cases is undiagnosed. According to Stitzel, the statistics are even worse for veterans receiving care at VA clinics.

“Studies have found that one in four, or 24 percent, have the disease, and the increased diabetes incidence among U.S. children threatens to erode the pool of service-eligible individuals,” Stitzel says.

The U.S. Department of Defense has awarded a three-year grant totaling $2,816,877 to Stitzel and JAX Assistant Professor Duygu Ucar, Ph.D.Develops computational models using genome datasets to study gene regulation and identify hypotheses for genomic medicine.Duygu Ucar, Ph.D., to study how genetic variation in the population — especially DNA sequence differences linked to type 2 diabetes — affect the resilience and stress responses of islets, clusters of cells in the pancreas that include the insulin-producing beta cells.

Environmental risk factors such as a high-calorie, low-nutrient diet contribute to excess inflammation and increased oxidative stress in our bodies, two conditions implicated in the onset and progression of diabetes. “Both conditions impose stress on islet cells in the pancreas, which impairs their normal function,” Ucar says. “Several of the genetic variants that are associated with increased type 2 diabetes risk appear to change areas of the genome called regulatory elements that function like molecular switches to turn genes on or off in islet cells under different environmental conditions.”

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Using human islet samples obtained from 100 non-diabetic organ donors, the researchers will apply advanced sequencing and genome editing technologies to study how islet cells behave after exposure to oxidative and inflammatory stress, assess the beneficial or deleterious functions of the stress-activated genes and pathways, and determine how DNA sequence variations present in each of us alters these islet stress responses.

The knowledge gained from this project, Ucar says, “will enable us to identify individuals at increased risk for abnormal islet stress responses and type 2 diabetes, as well as pinpointing the genes and pathways that can be targeted in future studies to correct impaired islet stress responses. These are the first critical steps to more precise, targeted diagnosis, treatment and prevention of type 2 diabetes.”

“Dissecting the Heterogeneity of Human Islet Stress Responses in Type 2 Diabetes,” U.S. Department of Defense grants W81XWH-1-0401 and W81XWH-1-0402