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

Abstract

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.

Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic β-cells

“…Several previous studies have demonstrated significant strain-specific differences in mice regarding insulin release ( 79 , 80 ), pancreas size and structure ( 81 ), and susceptibility to diabetes ( 79 – 84 ). However, our findings showing that female islets secrete more insulin that leads to a better glucose tolerance corroborate well both with human data ( 2 , 60 – 63 ) and several rodent studies ( 60 , 74 , 85 ). Additionally, a recent study demonstrated ( 74 ), also in the C57BL/6 background, that female islets respond with reduced Ca 2+ transients to glucose stimulation but increased β cell oscillatory responses compared with males, very similar to our previous ( 48 ) and current study.…”

“…However, our findings showing that female islets secrete more insulin that leads to a better glucose tolerance corroborate well both with human data ( 2 , 60 – 63 ) and several rodent studies ( 60 , 74 , 85 ). Additionally, a recent study demonstrated ( 74 ), also in the C57BL/6 background, that female islets respond with reduced Ca 2+ transients to glucose stimulation but increased β cell oscillatory responses compared with males, very similar to our previous ( 48 ) and current study. Nevertheless, while under basal glucose conditions female islets secreted more insulin, the stimulated insulin release was higher in males ( 74 ).…”

“…A caveat of our study is that we performed our analysis on mice 5 to 19 weeks old. Recently it has been shown that sex-specific pancreatic β cell mass and glucose tolerance are age dependent ( 74 ). Male mice showed glucose and insulin intolerance comparable to those of females at 3 and 6 months of age, while 6-month-old males displayed increased β cell mass in response to reduced insulin resistance compared with littermate females ( 74 ).…”

“…Recently it has been shown that sex-specific pancreatic β cell mass and glucose tolerance are age dependent ( 74 ). Male mice showed glucose and insulin intolerance comparable to those of females at 3 and 6 months of age, while 6-month-old males displayed increased β cell mass in response to reduced insulin resistance compared with littermate females ( 74 ). However, recently a different study reported that until 3 months both male and female C57BL/6 mice have similar insulin sensitivity ( 60 ).…”

ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin

“…Male mice were used because they have a higher β-cell mass and secrete more insulin in response to glucose than female mice and were therefore expected to display an enhanced response to IF 1 . 55 In conclusion, this study establishes that apoA-I restores insulin secretion in β-cells with disrupted cholesterol homeostasis by binding to an ectopic F1-ATPase β-subunit, internalizing into the cells and localizing to mitochondria where it decreases oxidative stress and enhances insulin secretion in response to glucose. Whether the observed increase in insulin secretion can be attributed to nuclear exclusion of pancreatic and duodenal homeobox 1, as reported previously, or whether it reflects improved processing of proinsulin to insulin and increased expression of the prohormone convertase 1/3 remains to be determined.…”