Utilizing a new genomic atlas of pancreatic cells from non-diabetic, prediabetic and diabetic people, researchers at The Jackson Laboratory (JAX) have identified dozens of unexpected genes linked to type 2 diabetes.
By analyzing hundreds of thousands of cells and pinpointing genes that behave differently in diseased versus healthy states, the team identified links between genetics and how pancreatic cells respond to stress as diabetes progresses.
“As a gene hunter, identifying the genes that contribute to disease is exciting because it gives us actionable information for precision medicine,” said JAX professor Michael Stitzel, a human geneticist who directed the research.
The new study, published in The EMBO Journal, focused on human pancreatic islets, with researchers analyzing nearly 250,000 islet cells from 48 human donors, characterizing each cell and identifying 14 distinct cell types.
The analysis showed people with type 2 diabetes (T2D) lose about 25% of their beta cells, the islet cells primarily responsible for insulin production. The team discovered 511 genes that were more or less active in beta cells from people with T2D. Genetic, protein, and metabolic analyses in mouse models narrowed that list to 58 genes that may contribute to beta cell defects linked to T2D.
Further experiments showed many of these genes could trigger increased beta cell death, suggesting they may play a direct role in the loss of glucose-regulating cells seen in people with the disease.
The team also discovered the genes GRAMD2B and PDZK1 appear to help maintain beta cell mass. A gene involved in insulin release, GRAMD2B levels were consistently lower in T2D. Deleting the same gene in mice led to glucose management problems. While deleting PDZK1in mice did not similarly disrupt glucose management, the team showed that reducing PDZK1 levels increased cell death in human islets.
“No one had previously shown these genes were relevant to type 2 diabetes,” said Khushdeep Bandesh, a staff scientist in the Stitzel lab who co-led the study.
Additionally, beta cells in T2D lowered the activity of a set of genes involved in vitamin A metabolism. These genes help convert dietary vitamin A into a molecule called retinoic acid, which helps beta cells survive stress. When the genes are less active, beta cells become more fragile and may die sooner. This points to previously underappreciated biology.
“This vitamin A pathway had been loosely linked to diabetes before, but this is the first time we’ve been able to clearly show at the gene level that it is systematically changing in type 2 diabetes,” Bandesh said. “What we don’t know, and what only careful clinical studies can answer, is whether interventions such as vitamin A supplementation would be helpful.”
Next, the researchers plan to expand their newly created database. Pancreatic islets are made up of several interacting cell types, and understanding how they communicate with one another is also crucial.
The research team has made their dataset available to the broader scientific community.