Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets.
Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets.
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DOI：
10.1038/s41598-017-02535-0
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发表时间：
2017-05-24
影响因子：
4.6
通讯作者：
Terauchi Y
中科院分区：
文献类型：
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作者：
Okuyama T;Shirakawa J;Yanagisawa H;Kyohara M;Yamazaki S;Tajima K;Togashi Y;Terauchi Y
葡萄糖激酶介导的葡萄糖信号传导诱导胰腺β细胞中的胰岛素分泌、增殖和凋亡。然而，这些过程背后的精确分子机制尚不清楚。在这里，我们证明了使用葡萄糖激酶激活剂（GKA）的葡萄糖激酶激活显著上调了分离的小鼠胰岛中Fibulin-5（Fbln 5）的表达，Fibulin-5是一种参与基质细胞信号传导的基质细胞蛋白。环境葡萄糖以时间和剂量依赖性方式诱导胰岛Fbln 5表达，并通过高脂饮食或胰岛素受体底物2（IRS-2）缺失进一步增强，而GKA诱导的Fbln 5表达增加在IRS-2缺陷胰岛中减少。葡萄糖激酶抑制剂、KATP通道开放剂、Ca 2+通道阻断剂和钙调磷酸酶抑制剂可减弱GKA诱导的胰岛Fbln 5上调，而双特异性酪氨酸磷酸化调节激酶（DYRK）1A抑制剂骆驼蓬碱可增强Fbln 5上调。尽管小鼠中Fbln 5的缺失对葡萄糖耐量或β细胞功能没有显著影响，但腺病毒介导的Fbln 5过表达增加了INS-1大鼠胰岛素瘤细胞中葡萄糖刺激的胰岛素分泌。由于胰岛Fbln 5的表达是通过葡萄糖激酶/KATP通道/钙调神经磷酸酶/活化T细胞核因子（NFAT）途径调节的，该途径对于维持β细胞功能至关重要，因此有必要进一步研究胰岛中Fbln 5的功能。
Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted.