Cytokine-mediated changes in K channel activity promotes an adaptive Ca response 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 Ca influx (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 Ca handling remain unknown. Here we investigated the role of K currents in cytokine-mediated β-cell dysfunction. K currents, 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 K currents were also examined as TALK-1 mediates K by facilitating [Ca] release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca] storage while maintaining 2 phase GSCI and GSIS. This adaptive Ca response was absent in TALK-1 KO islets, which exhibited decreased 2 phase GSCI and diminished GSIS. These findings suggest that K and TALK-1 currents play important roles in altered β-cell Ca 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 content to maintain GSIS.

MeSH Terms (25)

Adult Animals Calcium Female Gene Expression Regulation Glucose Humans Insulin Insulin-Secreting Cells Insulin Secretion Interferon-gamma Interleukin-1beta Ion Transport Islets of Langerhans Male Mice Mice, Inbred C57BL Mice, Knockout Potassium Potassium Channels, Tandem Pore Domain Primary Cell Culture RNA, Messenger Sarcoplasmic Reticulum Calcium-Transporting ATPases Tissue Culture Techniques Tumor Necrosis Factor-alpha

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