Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure

Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to fine-tune'' intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic beta cell mass and function is unclear. Here, we reveal that mice lacking beta cell OGT (beta OGT-KO) develop diabetes and beta cell failure. beta OGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of beta cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in beta OGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of beta OGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of beta cell mass and function and provide a direct link between O-GlcNAcylation and beta cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.