New Drug Target and Potential Biomarker for Beta Cell Regeneration

One of the most important goals of T1D research is to discover molecules that stimulate the growth of beta cells. Another goal: to find drugs that target those molecules. Now, JDRF-funded researchers, in collaboration with the pharmaceutical company Hoffmann-La Roche, have done both, discovering not only a protein that regulates beta cell growth, but also a drug that stimulates it.

The discovery, led by Markus Stoffel, M.D., Ph.D., a professor at the Swiss Federal Institute of Technology Zurich, represents a significant advance in identifying a new drug target for beta cell regeneration and potentially new biomarkers that can track the effectiveness of such a drug.

The work builds on a discovery made five years ago, when Dr. Stoffel and his team first showed that a once-obscure protein called transmembrane protein 27 (Tmem27) sits on the outer surface of beta cells. At the time, they found that the more Tmem27 was present on beta cells, the more beta cells were present in mice. They also found that when Tmem27 was snipped in two, the protein was completely inactivated, and fewer beta cells were present in the mice.

In other words, when Tmem27 is whole or intact, beta cells proliferate. When Tmem27 is cut in two, they do not.

“We hypothesized that if we could prevent Tmem27 from being snipped, we could get more beta cells to grow and proliferate,” says Dr. Stoffel, who is also a 2010 recipient of JDRF’s Gerold & Kayla Grodsky Basic Research Scientist Award. “This observation gave us the rationale to look for molecules that snip, and thus inactivate, Tmem27.”

After screening thousands of possible culprits, Dr. Stoffel and his team found the molecular scissors they were looking for: beta-site APP-cleaving enzyme 2 (Bace2), which cuts Tmem27 at the exact same spot on the protein every time. To confirm the role of Tmem27, mice were genetically engineered such that they lacked the molecular scissors. These mice were found to have larger islets and higher numbers of beta cells within those islets. Not only were there improvements in beta cell size and function, but the genetically engineered mice lacking the Bace2 gene were able to metabolize and clear glucose from the blood more efficiently than control mice with Bace2. These findings suggest that an inhibitor of Bace2 might be useful for promoting beta cell regeneration.

Having found the molecule responsible for inactivating Tmem27, Dr. Stoffel and his team wanted to find compounds to inhibit the enzyme to prevent Tmem27 cleavage. They worked with scientists at Hoffmann-La Roche to investigate chemical compounds that would inhibit Bace2. They found inhibitory compounds and showed that, when given to mice, those compounds inhibited Bace2 as expected and stimulated the proliferation of new beta cells.

In addition to identifying a new drug target for promoting beta cell regeneration, Dr. Stoffel’s research may also provide the basis for a new biomarker for monitoring the effectiveness of T1D treatments. Because Tmem27 floats into the bloodstream when it is clipped, scientists could develop a test to measure the number of Tmem27 fragments floating around the blood, and use this test to gauge the number of beta cells in the body.

“This is an exciting and potentially impactful finding,” says Patricia Kilian, Ph.D., scientific program director of regeneration research at JDRF. “It’s an example of how researchers make an early observation and follow up on it, and then take it to the next level, where it has translational potential—the potential to be developed into a drug that promotes the growth of beta cells for diabetes.”