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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.

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