Diabetes researchers have long believed that the disease starts when the immune system attacks insulin-producing beta cells in the pancreas. But that theory never made much sense to Anil Bhushan, Ph.D., a professor at the University of California, San Francisco, Diabetes Center. So he and a team of researchers in his lab probed the intricate biology of beta cells and made a discovery that he believes could be used to prevent the onset of the disease in people who are at high risk.
By studying nonobese diabetic mice, Bhushan’s team found that beta cells experience "secretory senescence," a process whereby DNA damage causes them to stop working properly. When that happens, they harm neighboring cells, which in turn causes the immune system to take notice and start attacking the entire insulin-producing system, namely beta cells.
What’s more, they found that an FDA-approved drug that eradicates senescent cells—AbbVie’s leukemia treatment Venclexta—can prevent the onset of diabetes in mouse models. They published their findings in the journal Cell Metabolism.
The team wanted to know if their findings might translate to people, so they studied beta cells from six people with early-stage diabetes and six healthy donors. The patients who had been diagnosed with diabetes had clear signs of secretory senescence. The researchers also found beta cell senescence in six people who had not been diagnosed with the disease but were considered at high risk because their blood tests showed early signs of an immune reaction to beta cells.
"Many results from these diabetic mouse lines have not panned out in humans, but the fact that we were seeing the very same markers of senescence in human pancreas tissue indicated that the same process is occurring in the human disease," said Peter Thompson, Ph.D., a postdoctoral researcher in Bhushan’s lab, in a statement.
But can eliminating senescent cells prevent Type 1 diabetes? To answer that question, the team turned to Venclexta, which is approved by the FDA to treat some leukemia patients. Venclexta targets senescent cells while leaving healthy tissues intact.
They found that when they gave the drug to mice predisposed to diabetes for two weeks prior to the onset of the disease, only 30% of the animals developed symptoms vs. 75% of mice who did not receive the medicine. They went on to discover that the drug had eliminated the senescent cells while leaving healthy beta cells intact.
Targeting senescent cells is an idea that has taken off in biotech, particularly among companies that are studying diseases of aging. Startups Cleara Biotech, for example, made headlines—and raised seed funding last year—after publishing preclinical research showing that its peptide treatment eliminated senescent cells in old mice, restoring physical function, kidney health and hair growth.
But most research efforts focused on Type 1 diabetes are geared towards regenerating beta cells. Just last week, Swiss researchers described a method they’re working on for converting human alpha and gamma endocrine cells into insulin-producing cells. And a University of Miami team has discovered a source of pancreatic stem cells that they believe could be coaxed to turn into insulin-producing cells.
Bhusan’s group aims to look further into the idea of holding off Type 1 diabetes altogether by targeting senescence. He envisions young people who are at risk of the disease taking a drug like Venclexta every once in a while to clear out senescent cells.
"There is great excitement about the potential of senolytic drugs to treat all kinds of diseases of aging," Bhushan said. "Our work is among the first to suggest that clearing senescent cells can also be beneficial in pathological conditions not related to aging, such as Type 1 diabetes."