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

Abstract

In humans, type 2 diabetes mellitus shows a higher prevalence in men compared with women, a phenotype that has been attributed to a lower peripheral insulin sensitivity in men. Whether sex-specific differences in pancreatic β cell function also contribute is largely unknown. Here, we characterized the electrophysiological properties of β cells in intact male and female mouse islets. Elevation of glucose concentration above 5 mM triggered an electrical activity with a similar glucose dependence in β cells of both sexes. However, female β cells had a more depolarized membrane potential and increased firing frequency compared with males. The higher membrane depolarization in female β cells was caused by approximately 50% smaller K v 2.1 K + currents compared with males but otherwise unchanged K ATP , large-conductance and small-conductance Ca 2+ -activated K + channels, and background TASK1/TALK1 K + current densities. In female β cells, the higher depolarization caused a membrane potential–dependent inactivation of the voltage-gated Ca 2+ channels (Ca V ), resulting in reduced Ca 2+ entry. Nevertheless, this reduced Ca 2+ influx was offset by a higher action potential firing frequency. Because exocytosis of insulin granules does not show a sex-specific difference, we conclude that the higher electrical activity promotes insulin release in females, improving glucose tolerance.