title: Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β 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 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.
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Emilyn U
authors.initials: EU
authors.lastname: Alejandro
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Bozadjieva
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Doga
authors.initials: D
authors.lastname: Kumusoglu
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdulhamid
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Levine
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Haataja
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Suryakiran
authors.initials: S
authors.lastname: Vadrevu
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109-0678, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI 48109-0678, USA. Electronic address: ebernalm@med.miami.edu.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000375:Aging; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism / Q000662:veterinary; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D007328:Insulin; D051742:Transcription Factor CHOP; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D051057:Proto-Oncogene Proteins c-akt; D000117:Acetylglucosamine