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Cytokine-mediated changes in Kchannel activity promotes an adaptive Caresponse that sustains β-cell insulin secretion during inflammation.

Dickerson MT, Bogart AM, Altman MK, Milian SC, Jordan KL, Dadi PK, Jacobson DA
Sci Rep. 2018 8 (1): 1158

PMID: 29348619 · PMCID: PMC5773563 · DOI:10.1038/s41598-018-19600-x

Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Cainflux (GSCI) and endoplasmic reticulum (ER) Ca([Ca]) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Cahandling remain unknown. Here we investigated the role of Kcurrents in cytokine-mediated β-cell dysfunction. Kcurrents, which control the termination of intracellular Ca([Ca]) oscillations, were reduced following cytokine exposure. As a consequence, [Ca]and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca]and decreased GSCI. The effect of cytokines on TALK-1 Kcurrents were also examined as TALK-1 mediates Kby facilitating [Ca]release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca]storage while maintaining 2phase GSCI and GSIS. This adaptive Caresponse was absent in TALK-1 KO islets, which exhibited decreased 2phase GSCI and diminished GSIS. These findings suggest that Kand TALK-1 currents play important roles in altered β-cell Cahandling 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 Cacontent to maintain GSIS.

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