School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
In Vivo Research Center, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
J Cell Physiol. 2018 Nov;233(11):8701-8710. doi: 10.1002/jcp.26750. Epub 2018 May 24.
The zafirlukast has been reported to be anti-inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic β-cells has not been investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration-dependent manner in both low and high glucose conditions and elevated the level of [Ca ] , further activating Ca /calmodulin-dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) signaling. These effects were nearly abolished by the L-type Ca channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca rather than intracellular Ca from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes.
扎鲁司特已被报道具有抗炎作用，并广泛用于缓解哮喘症状。然而，其对胰岛β细胞胰岛素分泌的影响尚未被研究。在此，我们研究了扎鲁司特对胰岛素分泌的影响及其潜在的机制。在半胱氨酰白三烯受体 1 拮抗剂中，只有扎鲁司特在低葡萄糖和高葡萄糖条件下以浓度依赖的方式增强胰岛素分泌，并升高[Ca 2+ ]水平，进一步激活钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）、蛋白激酶 B（AKT）和细胞外信号调节激酶（ERK）信号通路。这些作用几乎被 L 型钙通道拮抗剂硝苯地平所阻断，而肌浆/内质网 Ca 2+ -ATP 酶抑制剂 thapsigargin 则没有相同的作用，这表明扎鲁司特主要诱导细胞外 Ca 2+ 的进入，而不是内质网内的 Ca 2+ 。扎鲁司特治疗可显著降低 C57BL/6J 小鼠的血糖水平并增加胰岛素分泌。这些发现将有助于更好地理解扎鲁司特的副作用，并为糖尿病的治疗干预提供潜在的候选药物。
