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

ABSTRACT: 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 ? cell mass and function is unclear. Here, we reveal that mice lacking ? cell OGT (?OGT-KO) develop diabetes and ? cell failure. ?OGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of ? cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in ?OGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of ?OGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of ? cell mass and function and provide a direct link between O-GlcNAcylation and ? cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.

SUBMITTER: Alejandro EU 

PROVIDER: S-EPMC4839001 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature