KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.

Zheng-Da Pang, Yan Wang, Xiao-Jing Wang, Gang She, Xiao-Zhen Ma, Zheng Song, Li-Mei Zhao, Hui-Fang Wang, Bao-Chang Lai, Wei Gou, Xiao-Jun Du, Xiu-Ling Deng

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2019 Dec

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Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate-conductance calcium-activated K+ (KCa3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of KCa3.1 in pancreatic β cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific KCa3.1 channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of KCa3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of β-cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic β cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the KCa3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM-34 or a NF-κB inhibitor pyrrolidinedithiocarbamate. Additionally, expression of KCa3.1 in pancreas islet cells was up-regulated by activation of NF-κB with IL-1β stimulation. In summary, up-regulated KCa3.1 due to activation of NF-κB pathway leads to pancreatic inflammation via expression and secretion of chemokines and cytokines by pancreatic β cells, thereby facilitating progression of T2DM.-Pang, Z.-D., Wang, Y., Wang, X.-J., She, G., Ma, X.-Z., Song, Z., Zhao, L.-M., Wang, H.-F., Lai, B.-C., Gou, W., Du, X.-J., Deng, X.-L. KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus.

Citation

Zheng-Da Pang, Yan Wang, Xiao-Jing Wang, Gang She, Xiao-Zhen Ma, Zheng Song, Li-Mei Zhao, Hui-Fang Wang, Bao-Chang Lai, Wei Gou, Xiao-Jun Du, Xiu-Ling Deng. KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 Dec;33(12):14760-14771