Department of Cardiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, PR China.
Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, PR China.
Cell Signal. 2018 Jun;46:129-134. doi: 10.1016/j.cellsig.2018.02.002. Epub 2018 Feb 2.
Insulin resistance is an important pathological hallmark of type 2 diabetes mellitus. Glucose-stimulated insulin secretion (GSIS) plays a key role in maintaining blood glucose levels within normal range. Impaired GSIS has been associated with type 2 diabetes, however, the underlying molecular mechanisms remain largely unknown. Cysteinyl leukotriene receptor 1 (cysLT1R) is an important G protein-coupled receptor mediating the biological functions of cysteinyl leukotrienes (cys-LTs). Little is known about the effects of cysLT1R in insulin secretion and pathogenesis of T2DM. In the present study, we aimed to define the physiological functions of cysLT1R in GSIS in MIN6 β-cells. Using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, we found that cysLT1R was expressed in pancreatic MIN6 β-cells. We also reported that glucose increased the expression of cysLT1R in MIN6 cells. Additionally, the cysLT1R antagonist montelukast promoted GSIS in a dose dependent manner, however, the cysLT1R agonist LD4 inhibited GSIS, suggesting an antagonistic effect of cysLT1R on GSIS. Silencing of cysLT1R by transfection with cysLT1R siRNA enhanced GSIS while overexpression of cysLT1R reduced GSIS in pancreatic MIN6 β-cells. Mechanistically, we found that the Arf6/Cdc42/Rac1 pathway was involved in this process. Collectively, our findings highlight the essential role of cysLT1R in suppressing pancreatic insulin secretion, and potentially provided a new insight into understanding the mechanical regulation of glucose homeostasis.
胰岛素抵抗是 2 型糖尿病的重要病理标志。葡萄糖刺激的胰岛素分泌 (GSIS) 在维持血糖水平在正常范围内发挥着关键作用。GSIS 受损与 2 型糖尿病有关，但潜在的分子机制仍知之甚少。半胱氨酰白三烯受体 1 (cysLT1R) 是一种重要的 G 蛋白偶联受体，介导半胱氨酰白三烯 (cys-LTs) 的生物学功能。关于 cysLT1R 在胰岛素分泌和 2 型糖尿病发病机制中的作用知之甚少。在本研究中，我们旨在确定 cysLT1R 在 MIN6 β 细胞 GSIS 中的生理功能。通过逆转录聚合酶链反应 (RT-PCR) 和 Western blot 分析，我们发现 cysLT1R 在胰腺 MIN6 β 细胞中表达。我们还报道葡萄糖增加了 MIN6 细胞中 cysLT1R 的表达。此外，cysLT1R 拮抗剂孟鲁司特以剂量依赖的方式促进 GSIS，而 cysLT1R 激动剂 LD4 抑制 GSIS，表明 cysLT1R 对 GSIS 具有拮抗作用。通过转染 cysLT1R siRNA 沉默 cysLT1R 增强了 GSIS，而过表达 cysLT1R 则降低了胰腺 MIN6 β 细胞中的 GSIS。在机制上，我们发现 Arf6/Cdc42/Rac1 通路参与了这一过程。总之，我们的研究结果强调了 cysLT1R 在抑制胰腺胰岛素分泌中的重要作用，并为理解葡萄糖稳态的机械调节提供了新的见解。
