Sex Differences in Pancreatic β-Cell Physiology and Glucose Homeostasis in C57BL/6J Mice

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. Although 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 β-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 nonfasted blood glucose and insulin levels compared with male mice at 3 and 6 months of age. Both male and female animals show β-cell mass expansion from embryonic day 17.5 to adulthood, and no sex differences were observed at embryonic day 17.5, newborn, 1 month, or 3 months of age. However, 6-month-old males displayed increased β-cell mass in response to insulin resistance compared with littermate females. Molecularly, we uncovered sexual dimorphic alterations in the protein levels of nutrient sensing proteins O-GlcNAc transferase and mTOR, as well as differences in glucose-stimulus coupling mechanisms that may underlie the differences in sexually dimorphic β-cell physiology observed in C57BL/6J mice.