Pancreatic Beta Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Streptozotocin- and High-Fat Diet–Induced Diabetes in Female Mice

Abstract

The nutrient-sensor O-GlcNAc transferase (OGT), the sole enzyme that adds an O-GlcNAc-modification onto proteins, was shown to regulate β-cell survival and function as β-cell deletion of OGT induces diabetes and islet failure in mice. We hypothesized that β-cell OGT overexpression (Rip-cre;OgtOE) would confer protection from streptozotocin (STZ)-induced β-cell failure and high-fat diet (HFD)-induced diabetes. Female mice are typically resistant from HFD- or STZ-induced diabetes. However, the molecular mechanisms underlying this sexual dimorphism are unclear. Here, we uncovered that Rip-cre;OgtOE mice show normal peripheral insulin sensitivity and glucose tolerance in normal chow but when challenged female transgenic mice alone develop glucose intolerance post 8-weeks of HFD and severe hyperglycemia 1-week post STZ treatment. Surprisingly, male transgenic mice are neither protected nor impaired when compared to controls in both treatments. Molecular interrogation of islets validated efficient overexpression of OGT in both sexes by confirming protein expression of the reporter transgene (GFP). However, significant increase in OGT protein was observed only in islets of female Rip-cre;OgtOE mice, suggesting sex difference in OGT protein regulation. Transcriptome analysis by RNA sequencing shows increased expression levels of genes involved in acute inflammation (Ggt5, Ncf1, Ptgs1, Alox5ap) and immune response via agranulocyte adhesion and diapedesis (Glycam1) in islets of female Rip-cre;OgtOE mice, providing a mechanism of susceptibility to STZ and HFD-induced islet failure. Indeed, pancreas analysis shows increased islet infiltrating lymphocytes in female Rip-cre;OgtOE compared to control post 22 weeks of HFD treatment. Together, these data highlight the novel role of OGT in inflammation induced by STZ and HFD in islets and emphasize the importance of OGT dosage and O-GlcNAc cycling in β-cell survival. Disclosure R. Mohan: None. H. Ruan: None. X. Yang: None. E. Alejandro: None.