Pancreatic β-cell O-GlcNAc transferase overexpression increases susceptibility to metabolic stressors in female mice

Ramkumar Mohan, Seokwon Jo, Elina da Sol Chung, Eunice Oribamise, Amber Lockridge, Juan E. Abrahante-Lloréns, Hai Bin Ruan, Xiao Yong Yang, Emilyn U. Alejandro

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) mice, where a significant increase in Ogt protein level and O-GlcNAc-modification of proteins were observed in islets under a normal chow diet. We uncovered that βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozy-gous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE Hz mice developed hyperglycemia and glucose intolerance post-STZ treatment. Transcriptome analysis between islets with loss or gain of Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk and Akt and inflammatory regulators IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis.

Original languageEnglish (US)
Article number2801
Issue number10
StatePublished - Oct 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grant NIDDK (R21DK112144 and R01DK115720) to E.U.A.; and Regenerative Medicine Minnesota and McKnight Foundation (University of Minnesota) to E.U.A.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Islet
  • O-GlcNAc transferase
  • Streptozocin

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural


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