According to a new study by Weill Cornell Medicine researchers, a drug currently in clinical trials as a cancer therapy can also stimulate pancreatic beta cells to secrete insulin, revealing a previously unknown mechanism for insulin regulation in type 2 diabetes. The preclinical discovery, which was published in Nature Chemical Biology, provides a new chemical tool for probing the biology of diabetes and could lead to better treatments.
“We’ve known about insulin for a century, but there are still a lot of things we don’t know about the major mechanisms controlling insulin secretion,” said senior author Dr. Shuibing Chen, director of the Center for Genomic Health and the Kilts Family Professor of Surgery at Weill Cornell Medicine.
To search for new insulin-regulating mechanisms, Dr. Chen and her colleagues, including first author Dr. Angie Chi Nok Chong, a postdoctoral associate in Dr. Chen’s lab, began by testing a library of drugs on cultures of mouse pancreatic beta cells, looking for compounds that stimulated insulin secretion in response to glucose.
Instead of running a large-scale drug screening, we decided to do a focused library. So, we had candidates that we knew might be involved in certain important biological processes.
Dr. Shuibing Chen
“Instead of running a large-scale drug screening, we decided to do a focused library,” said Dr. Chen who is also a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. “So, we had candidates that we knew might be involved in certain important biological processes.”
The screening revealed three compounds that increased insulin secretion, two of which targeted known insulin-regulating mechanisms in pancreatic beta cells. A third, on the other hand, targeted a protein called CHEK2, which is frequently mutated in cancer but had not previously been linked to glucose metabolism.
The researchers confirmed that the compound increases glucose-mediated insulin secretion in multiple tests on human and non-human pancreatic cells grown in the lab, as well as various mouse models of type 2 diabetes, with collaborators from two other institutions. “That makes the data very exciting, because it’s really consistent from mouse to human islets in vitro, as well as both mouse and nonhuman primate in vivo,” Dr. Chen said.
Probing the mechanism more closely, the team uncovered a previously unknown insulin secretion-regulating molecular pathway that operates in multiple mammalian species. Dr. Chen says the compound they identified in their initial screen, called AZD7762, promises to be a useful tool for exploring other aspects of insulin regulation.
“We not only identified CHEK2 as a potential drug target; we can also use AZD7762 as a chemical probe to find new mechanisms for insulin secretion, and find new targets in the future,” she said.
While AZD7762 is currently being studied as a cancer therapy, it is unlikely that it will be directly translated into a new diabetes treatment. “The safety requirement for cancer therapy and diabetes therapy is completely different,” Dr. Chen explained, adding that the cancer drug’s side effects would likely make it unsuitable for long-term use in a chronic condition like type 2 diabetes. Compounds that affect CHEK2 only in pancreatic beta cells, on the other hand, could be extremely effective.
“If we can target delivery of the drugs to beta cells without affecting other cells, that could be an interesting approach to probe,” said Dr. Chen.
In addition, the project has laid the groundwork for future drug development. “We built up the foundation for the chemical screening and testing in animal and cell models,” Dr. Chen went on to say. “In the future if we find anything interesting, it can be immediately tested in this pipeline.”
