The Role of the O-GlcNAc-post-translational modification on β-cell identity
Type II diabetes onset is characterized by a decrease in insulin production by the β-cells in the pancreas. One reason β-cells may stop producing insulin is due to the loss of β-cell identity and the acquisition of α-cell fate, in a process known as differentiation. Transcription factor Pdx1 is a master regulator of β-cell identity. As a transcription factor, Pdx1 localizes to the nucleus to perform its function on the genome. Pdx1 is post-translationally modified by Ogt, the enzyme that adds an O-GlcNAc (O-linked N-Acetylglucosamine) sugar onto Ser and Thr residues of nuclear, cytosolic, and mitochondrial proteins. O-GlcNAc modification on Pdx1 is associated with increased DNA binding affinity. In both pancreases and islets lacking Ogt, Pdx1 protein level is reduced. This suggests a relationship between O-GlcNAcylation and Pdx1. However, the links between O-GlcNAcylation, β-cell identity, and Pdx1 localization are unexplored. We hypothesize that Ogt regulates β-cell identity by affecting Pdx1 localization. Pancreases of Ogt knockout mice were assessed for β-cell mass, α-cell mass, the occurrence of bihormonal cells, and Pdx1 localization. Mice with β-cell Pdx1 overexpression in the background of Ogt loss were also studied to determine the effect of normalizing Pdx1 protein.
Here, I show that Ogt may play a role in maintaining β-cell identity via regulation of Pdx1 localization. Ogt knockout mice showed a trend towards an increased number of bihormonal cells and a significant increase in cytoplasmically localized Pdx1 in the pancreatic islets. Deletion of Ogt in β-cells resulted in no difference in β-cell or α-cell mass compared to controls in p30 mice, recapitulating published data. This demonstrates that at day 30, Ogt knockout mice have not yet developed the diabetic phenotypes associated with hyperglycemia. Overall, the results of this study are a step towards understanding the mechanism behind the loss of β-cell identity and the role that Ogt and Pdx1 play in it. Understanding how β-cell loss occurs may provide insight into the development, onset, and potential treatments for Type 2 Diabetes.