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

Sci Rep. 2018 Jan 18;8(1):1158. doi: 10.1038/s41598-018-19600-x.

Abstract

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. Kslow 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 Kslow by facilitating [Ca2+]ER release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca2+]ER storage while maintaining 2nd phase GSCI and GSIS. This adaptive Ca2+ response was absent in TALK-1 KO islets, which exhibited decreased 2nd phase GSCI and diminished GSIS. These findings suggest that Kslow 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • IL1B protein, human
  • Insulin
  • Interleukin-1beta
  • KCNK16 protein, human
  • Potassium Channels, Tandem Pore Domain
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human
  • Glucose
  • Potassium
  • Calcium