The outer membrane of cells is a highly specialized compartment that contains a number of molecules regulating cell-cell communication and intra-cellular signaling. Dr. Stoffel’s group had previously identified Tmem27 as a protein residing in the beta cell’s outer membrane that acts to regulate insulin secretion and beta cell proliferation. Tmem27’s activity can be turned off by a cleavage event that sheds the extracellular portion of Tmem27. Dr. Stoffel had shown that preventing Tmem27 shedding is sufficient to increase beta cell function and proliferation. In the present study, Dr. Stoffel and his team have identified Bace2 as the enzyme responsible for Tmem27 shedding and demonstrate that inhibition of Bace2, either genetically or using a novel small-molecule Bace2 inhibitor, is sufficient to increase Tmem27 levels, increase beta cell mass and improve glucose control in diabetic animals. These studies further validate Tmem27 as a target for promoting beta cell regeneration and identify Bace2 as a potential drug target to increase Tmem27 activity in beta cells.
Esterházy, D., Stützer, I., Wang, H. et al. (2011). Bace2 Is a Beta Cell-Enriched Protease that Regulates Pancreatic Beta Cell Function and Mass. Cell Metab 14, 365-377.
Ramifications for Individuals with Type 1 Diabetes:
This work has identified Bace2 as a potential drug target and small molecule capable of driving expansion of beta cell mass. Further preclinical work will be required to better understand the mechanism of action, optimize the compound and evaluate the safety and pharmacological properties of the compound before clinical studies could be considered.
This work was supported in part by a JDRF Strategic Research Agreement and Scholar Award to Dr. Stoffel.