Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells
Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells
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DOI：
10.1111/bph.12194
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发表时间：
2013-07-01
影响因子：
7.3
通讯作者：
Oiry, C.
中科院分区：
文献类型：
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作者：
Bardy, G.;Virsolvy, A.;Oiry, C.
背景与目的栎素是一种天然的多酚类黄酮类化合物，在体内具有抗糖尿病的作用。其对分泌胰岛素的β细胞的作用机制鲜有文献记载。在这项工作中，我们分析了在没有任何共刺激因子的情况下，槲皮素对胰岛细胞胰岛素分泌和细胞内钙离子浓度([Ca~(2+)](I))的影响。在INS-1细胞系和大鼠离体胰岛上进行了实验方法实验。均相时间分辨荧光法测定胰岛素释放量。[Ca~(2+)](I)的变化用比率荧光指示剂Fura-2测定。采用全细胞膜片钳技术记录钙通道电流。关键结果：槲皮素呈浓度依赖性增加胰岛素分泌和升高[Ca~(2+)](I)。这些作用不能被SERCA抑制剂thapsigarin(1mU中心点L-1)所改变，但几乎被L型钙通道拮抗剂硝苯地平(1mU中心点L-1)所阻断。与L型钙通道激动剂Bay K8644类似，槲皮素通过使L型钙电流的电压依赖性激活移向负电位，使其[Ca~(2+)]_(I)升高，胰岛素分泌增加。在最大活性浓度的BeK8644(1 mU分子中心点L-1)存在下，槲皮素的作用不受抑制，这两种药物对[Ca~(2+)](I)有累积作用。结论与意义综合考虑，我们的结果表明，与Bay K8644不同的是，槲皮素通过与L型钙通道相互作用增加钙内流，从而刺激胰岛素的分泌。这些数据有助于更好地了解槲皮素对胰岛素分泌的作用机制。
Background and Purpose Quercetin is a natural polyphenolic flavonoid that displays anti-diabetic properties in vivo. Its mechanism of action on insulin-secreting beta cells is poorly documented. In this work, we have analysed the effects of quercetin both on insulin secretion and on the intracellular calcium concentration ([Ca2+](i)) in beta cells, in the absence of any co-stimulating factor. Experimental Approach Experiments were performed on both INS-1 cell line and rat isolated pancreatic islets. Insulin release was quantified by the homogeneous time-resolved fluorescence method. Variations in [Ca2+](i) were measured using the ratiometric fluorescent Ca2+ indicator Fura-2. Ca2+ channel currents were recorded with the whole-cell patch-clamp technique. Key Results Quercetin concentration-dependently increased insulin secretion and elevated [Ca2+](i). These effects were not modified by the SERCA inhibitor thapsigargin (1 mu mol center dot L-1), but were nearly abolished by the L-type Ca2+ channel antagonist nifedipine (1 mu mol center dot L-1). Similar to the L-type Ca2+ channel agonist Bay K 8644, quercetin enhanced the L-type Ca2+ current by shifting its voltage-dependent activation towards negative potentials, leading to the increase in [Ca2+](i) and insulin secretion. The effects of quercetin were not inhibited in the presence of a maximally active concentration of Bay K 8644 (1 mu mol center dot L-1), with the two drugs having cumulative effects on [Ca2+](i). Conclusions and Implications Taken together, our results show that quercetin stimulates insulin secretion by increasing Ca2+ influx through an interaction with L-type Ca2+ channels at a site different from that of Bay K 8644. These data contribute to a better understanding of quercetin's mechanism of action on insulin secretion.