Molecular mechanisms responsible for the sexual dimorphism in pancreatic β-cell insulin release: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

In humans, type 2 diabetes mellitus (T2DM) has a higher incidence in males compared to females, a phenotype recapitulated by many rodent models. While the sex difference in insulin sensitivity partially accounts for this phenomenon, hitherto uncharacterized differences in pancreatic β-cell insulin release strongly contribute. Here, we show that stepwise increase in extracellular glucose concentration (2, 5, 7.5, 10, 15, 20 mM) induced electrical activity in β cells of both sexes with similar glucose sensitivity (female, EC₅₀ = 9.45 ± 0.15 mM; male, EC₅₀ = 9.42 ± 0.16 mM). However, female β cells’ resting membrane potential (RMP) and inter-spike potential (IP) were significantly higher compared to males (e.g., at 15 mM glucose: male RMP = −82.7 ± 6.3, IP = −74.3 ± 6.8 mV; female RMP = −50.0 ± 7.1, IP = −41.2 ± 7.3 mV). Females also showed higher frequency of trains of action potential (AP; at 10 mM glucose: male F = 1.13 ± 0.15 trains/min; female F = 1.78 ± 0.25 trains/min) and longer AP-burst duration (e.g., at 10 mM glucose: male, 241 ± 30.8 ms; female, 419 ± 60.2 ms). The higher RMP in females reduced the voltage-gated calcium channel (Ca_V) availability by ∼60%. This explains the paradoxical observation that, despite identical Ca_V expression levels and higher electrical activity, the islet Ca²⁺ transients were smaller in females compared to males. Interestingly, the different RMPs are not caused by altered K_ATP, TASK, or TALK K⁺ currents. However, stromatoxin-1–sensitive K_V2.1 K⁺ current amplitude was almost double in males (I_K = 130.93 ± 7.05 pA/pF) compared to females (I_K = 75.85 ± 11.3 pA/pF) when measured at +80 mV. Our results are in agreement with previous findings showing that K_V2.1 genetic deletion or pharmacological block leads to higher insulin release and β-cell survival. Therefore, we propose the sex-specific expression of K_V2.1 to be the mechanism underlying the observed sexual dimorphism in insulin release and the incidence of T2DM.