K(Ca)3.1 channel mediates inflammatory signaling of pancreatic beta cells and progression of type 2 diabetes mellitus

Article

关键词: ACTIVATED POTASSIUM CHANNEL;    K+ CHANNEL;    KAPPA-B;    GLUCOSE;    INHIBITOR;    CHEMOKINE;    BLOCKADE;    PROTEIN;    KCA3.1;    RISK;   

DOI  :  10.1096/fj.201901329RR

来源: SCIE

【 摘 要 】

Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate-conductance calcium-activated K+ (K(Ca)3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of K(Ca)3.1 in pancreatic beta cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific K(Ca)3.1 channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of K(Ca)3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of beta-cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic 13 cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the K(Ca)3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM-34 or a NF-kappa B inhibitor pyrrolidinedithiocarbamate. Additionally, expression of K(Ca)3.1 in pancreas islet cells was up-regulated by activation of NF-kappa B with IL-1 beta stimulation. In summary, up-regulated K(Ca)3.1 due to activation of NF-kappa B pathway leads to pancreatic inflammation via expression and secretion of chemokines and cytokines by pancreatic beta cells, thereby facilitating progression of T2DM.

【 授权许可】

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