WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic -Cells

WASH is an endosomal protein belonging to the Wiskott-Aldrich syndrome protein superfamily that participates in endosomal receptor trafficking by facilitating tubule fission via activation of the ubiquitously expressed Arp2/3 complex. While several studies have begun to elucidate an understanding of the functions of WASH in cells lines, the in vivo function of WASH has not been fully elucidated, since total body deletion in mice leads to early embryonic lethality. To circumvent this problem, we have used a WASH conditional knockout mouse model to investigate the role of WASH in the pancreas. We find that pancreas-specific deletion of WASH leads to impaired blood glucose clearance and reduced insulin release upon glucose stimulation. Furthermore, WASH depletion results in impaired trafficking of Glut2 in pancreatic -cells as a consequence of an intracellular accumulation of Glut2 and overall decreased levels of Glut2 protein. Taken together, these results indicate that WASH participates in pancreatic -cell glucose sensing and whole-body glucose homeostasis. Thus, patients harboring mutations in components of the WASH complex could be at risk for developing type 2 diabetes.