Cytokine-mediated changes in K⁺ channel activity promotes an adaptive Ca²⁺ response that sustains β-cell insulin...

Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Ca²⁺ influx (GSCI) and endoplasmic reticulum (ER) Ca²⁺ ([Ca²⁺]_ER) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Ca²⁺ handling remain unknown. Here we investigated the role of K⁺ currents in cytokine-mediated β-cell dysfunction. K_slow currents, which control the termination of intracellular Ca²⁺ ([Ca²⁺]_i) oscillations, were reduced following cytokine exposure. As a consequence, [Ca²⁺]_i and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca²⁺]_i and decreased GSCI. The effect of cytokines on TALK-1 K⁺ currents were also examined as TALK-1 mediates K_slow by facilitating [Ca²⁺]_ER release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca²⁺]_ER storage while maintaining 2^nd phase GSCI and GSIS. This adaptive Ca²⁺ response was absent in TALK-1 KO islets, which exhibited decreased 2^nd phase GSCI and diminished GSIS. These findings suggest that K_slow and TALK-1 currents play important roles in altered β-cell Ca²⁺ handling and electrical activity during low-grade inflammation. These results also reveal that a cytokine-mediated reduction in TALK-1 serves an acute protective role in β-cells by facilitating increased Ca²⁺ content to maintain GSIS.