The importance of sexual dimorphism has been highlighted in recent years since the National Institutes of Health’s mandate on considering sex as a biological variable. While recent studies have taken strides to study both sexes side by side, investigations into the normal physiological differences between males and females are limited. In this study, we aimed to characterized sex-dependent differences in glucose metabolism and pancreatic beta cell physiology in normal conditions using C57BL/6J mice, the most common mouse strain used in metabolic studies. Here we report that female mice have improved glucose and insulin tolerance associated with lower non-fasted blood glucose and insulin levels compared to male mice at 3 and 6 month of age. Both male and female animals show beta cell mass expansion from e17.5 to adulthood, and no sex differences were observed at e17.5, newborn, 1 month, or 3 months of age. However, 6-month old males displayed increased beta cell mass in response to insulin resistance compared to littermate females. Molecularly, we uncovered sexual dimorphic alterations in the protein levels of nutrient sensing proteins Ogt and mTOR, as well as differences in glucose-stimulus coupling mechanisms that may underlie the differences in sexually dimorphic beta cell physiology observed in C57BL/6J 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 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 (homozygous) 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.

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