Blocking cellular pathway delays or prevents onset of diabetes in mice
Type 1 diabetes begins when beta cells in the pancreas die off, meaning a patient can no longer produce enough insulin. Scientists have now identified a cellular pathway that can contribute to the death of these cells, and found that blocking it in mice and human cells keeps the beta cells alive for longer, delaying or preventing the onset of diabetes.
Unlike type 2 diabetes, type 1 can’t be prevented by lifestyle changes. It’s usually triggered when the immune system mistakenly begins attacking insulin-producing cells in the pancreas, which then reduces the levels of that hormone in the patient’s blood. That in turn affects their ability to regulate blood sugar, requiring regular insulin shots to manage the condition.
In the new study, researchers from Boston Children’s Hospital and the Unviersity of Milan identified a cellular pathway that may play a role as well. The team found that when a protein called IGFBP3 binds to a receptor called TMEM219 on beta cells, it triggers a cell death process.
"We believe this might be a natural mechanism to keep the beta cell population under control," said Paolo Fiorina, co-lead author of the study. "We think that in disease, IGFBP3 production may be increased, so there is a loss of beta cells.”
Sure enough, the researchers detected higher levels of IGFBP3 in the blood of people with both type 1 and type 2 diabetes than in nondiabetic people. Levels were also elevated in people at risk for developing the disease.
With this pathway in their sights, the researchers then explored whether blocking it could prevent beta cells from dying. In tests in mouse models of diabetes, the team tried three different methods – blocking the IGFBP3 protein, editing beta cells to delete the gene for the TMEM219 receptor, or using a recombinant protein based on part of the receptor.
In all of these test groups, the team found that more beta cells survived, resulting in increased insulin production and effectively a delay or even prevention of diabetes developing.
Follow-up studies investigated whether this pathway might play a similar role in humans. The team examined pancreatic islets – the part of the organ containing beta cells – from human cadavers. Exposure to IGFBP3 induced higher rates of beta cell death, while blocking the pathway protected the cells and allowed them to continue producing insulin.
The team says this finding could potentially lead to new methods for treating or preventing type 1 diabetes. The first in-human tests of antibody treatments that target this pathway could begin in September this year.
The research was published in the journal Nature Communications.