Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass.

Decreased beta cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human beta cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented beta cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of beta cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic beta cell mass.