KCa3.1 channel mediates inflammatory signaling of pancreatic β-cells and progression of type 2 diabetes mellitus
KCa3.1 channel mediates inflammatory signaling of pancreatic β-cells and progression of type 2 diabetes mellitus
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KCa3.1 通道介导胰腺 β 细胞的炎症信号传导和 2 型糖尿病的进展
DOI：
10.1096/fj.201901329rr
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
邓秀玲
中科院分区：
文献类型：
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作者：
庞正达;王燕;王晓静;佘刚;马晓真;宋征;赵丽梅;王慧芳;来宝长;苟伟;杜晓军;邓秀玲
慢性胰岛炎症与2型糖尿病的发生有关。中电导钙激活钾通道（KCa3.1）在炎症性疾病中起重要作用。然而，胰腺β细胞中KCa3.1在2型糖尿病进展中的作用和调节仍不清楚。在本研究中，我们评估了特异性KCa 3.1通道阻断剂TRAM-34对db/db模型糖尿病表型的影响。在糖尿病小鼠中，阻断KCa3.1可显著改善糖耐量，增加餐后胰岛素水平的分泌，并通过减少炎症介质的表达和分泌来减少β细胞质量的损失。此外，在培养的胰腺癌细胞中，暴露于高水平的葡萄糖或棕榈酸显著增加了KCa 3.1通道的表达和电流密度，以及促炎趋化因子的分泌，并且这种作用类似地被TRAM-34或核因子-κB（NF-κB）抑制剂PDTC预孵育所逆转。此外，IL-1β刺激NF-κB活化可上调胰岛细胞KCa 3.1的表达。综上所述，NF-κB通路激活导致KCa 3.1上调，通过胰腺β细胞表达和分泌趋化因子和细胞因子导致胰腺炎症，从而促进2型糖尿病的进展。
Chronic islet inflammation is associated with development of type 2 diabetes mellitus. 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 type 2 diabetes mellitus remain unclarified. In the present study, we evaluated effect of the specific KCa3.1 channel blocker TRAM-34 on diabetic phenotype in 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 -cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of KCa3.1 channel, as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by pre-incubation with TRAM-34 or a nuclear factor-κB (NF-κB) inhibitor PDTC. Additionally, expression of KCa3.1 in pancreas islet cells was upregulated by activation of NF-κB with interleukin-1β stimulation. In conclusion, upregulated 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 type 2 diabetes mellitus.