Increased pancreatic β-cell electrical activity reduces diabetes susceptibility in female mice.

Abstract

In humans, the incidence of Type 2 Diabetes Mellitus (T2DM) in premenopausal women is higher compared to men, phenotype also recapitulated by many rodent models. The T2DM etiology involves impaired or total lack of insulin release from pancreatic β-cells. High voltage-gated Ca2+ channels (HVCCs) are multi-subunit protein complexes responsible for β-cell electrical activity and insulin vesicle exocytosis. Previously, we showed that genetic deletion of α2δ-1 HVCC auxiliary subunit equally reduced Ca2+ influx by 60% in β-cells of both males and females but caused diabetes only in males because female pancreatic islets released significantly more insulin (Mastrolia et al., 2017). Functional characterization shows that both male and female β-cells display a similar glucose-induced increase in the membrane potential under all stimulatory glucose levels (e.g. ≅10mM glucose RMPfemales= −64.7±5.8 mV; RMPmales= −63.1±3.6 mV) consistent with similar HVCC Ca2+ influx and KATP, Kv, BK and SK K+ effluxes. The glucose induced intracellular Ca2+ transients are also similar between sexes consistent with identical Ca2+-induced Ca2+-release and intracellular store Ca2+ content. However, females have a higher percentage of β-cells that respond to glucose stimulation with increased electrical activity (≅10 mM glucose 58% of male β-cells fire action potentials (AP) compared to 90% of female β-cells). Additionally, female β-cells displayed a higher frequency of glucose-induced AP-trains (≅10 mM, female β-cells 2.2±0.5 AP-trains/min, males 0.41±0.1, p<0.05). The increased electrical activity resulted in a significantly higher insulin release in females compared to males therefore lowering the risk of developing T2DM. Current experiments are on the way to elucidate the mechanism leading to the higher electrical activity in female β-cells. Support: FWF P31434, P36053, and DOC30-B30 to PT.