Cytokine-mediated changes in K(+) channel activity promotes an adaptive Ca(2+) response that sustains β-cell insulin secretion during inflammation

Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Ca(2+) influx (GSCI) and endoplasmic reticulum (ER) Ca(2+) ([Ca(2+)](ER)) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Ca(2+) 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 Ca(2+) ([Ca(2+)](i)) oscillations, were reduced following cytokine exposure. As a consequence, [Ca(2+)](i) and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca(2+)](i) and decreased GSCI. The effect of cytokines on TALK-1 K(+) currents were also examined as TALK-1 mediates K(slow) by facilitating [Ca(2+)](ER) release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca(2+)](ER) storage while maintaining 2(nd) phase GSCI and GSIS. This adaptive Ca(2+) 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 Ca(2+) 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 Ca(2+) content to maintain GSIS.