The discovery represents a significant advance in identifying a new drug target for beta cell regeneration.
This new advance is based on a discovery made five years ago, by the same team of researchers led by Dr. Stoffel a professor at the Swiss Federal Institute of Technology in Zurich. The team had found that increased levels of a protein, called Tmem27, on beta cells were associated with increased islet mass in mice. They also found that if Tmem27 is cleaved, it left the protein completely inactivated.
The researchers understood that if they could prevent Tmem27 from being cleaved and increase the levels of this protein, they could get more beta cell growth. After screening possible molecules that could snip Tmem27, Dr. Stoffel and his team found the culprit: Bace2, an enzyme protein that, like Tmem27, also resides on the outer surface (known as the plasma membrane) of the beta cell. The researchers confirmed their theory by finding that mice that lacked Bace2 had larger islets and the beta cells in the islets increased in number, a process known as proliferation or regeneration. They also found that these mice were able to clear glucose from the blood more efficiently than control mice with Bace2.
Dr. Stoffel and his team next aimed to inhibit Bace2 in an effort to control and promote the growth of beta cells. To do so, they teamed up with scientists at Hoffmann-LaRoche who developed a chemical compound that could inhibit Bace2. When the scientists gave this compound to mice, they saw that it inhibited Bace2 and stimulated the growth of new beta cells. Importantly, Bace2, and not its close relative Bace1, which is implicated in other diseases, cleaves the Tmem27 protein, suggesting the potential for developing a Bace2 inhibitor as a diabetes-specific therapy.
In addition to identifying a new drug target for promoting beta cell regeneration, Dr. Stoffel’s work may also help in developing tests to measure the amount of Tmem27 fragments in the blood – a biomarker that could be used as an index of beta cell number.
The work appears in the September 7 issue of Cell Metabolism.