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

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 beta cell function also contribute is largely unknown. Here, we characterized the electrophysiological properties of beta 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 beta cells of both sexes. However, female beta cells had a more depolarized membrane potential and increased firing frequency compared with males. The higher membrane depolarization in female beta cells was caused by approximately 50% smaller Kv2.1 K+ currents compared with males but otherwise unchanged KATP, large -conductance and small -conductance Ca2+-activated K+ channels, and background TASK1/TALK1 K+ current densities. In female beta cells, the higher depolarization caused a membrane potential-dependent inactivation of the voltage -gated Ca2+ channels (CaV), resulting in reduced Ca2+ entry. Nevertheless, this reduced Ca2+ 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.