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

Emilyn U. Alejandro, Nadejda Bozadjieva, Doga Kumusoglu, Sarah Abdulhamid, Hannah Levine, Leena Haataja, Suryakiran Vadrevu, Leslie S. Satin, Peter Arvan, Ernesto Bernal-Mizrachi

Research output: Contribution to journalArticle

18 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)2527-2538
Number of pages12
JournalCell Reports
Volume13
Issue number11
DOIs
StatePublished - Dec 22 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Alejandro, E. U., Bozadjieva, N., Kumusoglu, D., Abdulhamid, S., Levine, H., Haataja, L., Vadrevu, S., Satin, L. S., Arvan, P., & Bernal-Mizrachi, E. (2015). Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure. Cell Reports, 13(11), 2527-2538. https://doi.org/10.1016/j.celrep.2015.11.020