Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice

The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic beta-cell survival and insulin secretion. We hypothesized that beta-cell Ogt overexpression would confer protection from beta-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a beta-cell-specific Ogt in overexpressing (beta OgtOE) 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 beta OgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female beta OgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal beta-cell mass. While female mice are normally resistant to low-dose STZ treatments, the beta OgtOE 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 IL1 beta and NFk beta. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in beta-cell survival and function to regulate glucose homeostasis.

Automated summary

The study revealed that beta-cell Ogt overexpression in mice led to glucose intolerance under metabolic stressors such as high-fat diet and streptozocin, despite normal insulin secretion and beta-cell mass. Additionally, female mice with beta Ogt overexpression developed hyperglycemia and glucose intolerance post-treatment with streptozocin, contrary to the typical resistance seen in female mice. Transcriptional analysis showed common altered pathways involving pro-survival and inflammatory regulators in islets with loss or gain of Ogt. These findings suggest a gene dosage effect of Ogt and highlight the importance of O-GlcNAc cycling in beta-cell survival and function for glucose homeostasis.