Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan.
Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan.
Sci Rep. 2017 May 24;7(1):2364. doi: 10.1038/s41598-017-02535-0.
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, K channel opener, Ca 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/K 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.
葡萄糖激酶介导的葡萄糖信号转导可诱导胰岛β细胞胰岛素分泌、增殖和凋亡。然而，这些过程的确切分子机制尚不清楚。在这里，我们证明使用葡萄糖激酶激活剂 (GKA) 激活葡萄糖激酶可显著上调分离的小鼠胰岛中细胞外基质-细胞信号转导相关的细胞外基质蛋白 5 (Fbln5) 的表达。胰岛 Fbln5 的表达受环境葡萄糖的时间和剂量依赖性诱导，并可进一步被高脂肪饮食或胰岛素受体底物 2 (IRS-2) 缺失增强，而 GKA 诱导的 Fbln5 表达增加在 IRS-2 缺陷型胰岛中被减弱。GKA 诱导的胰岛 Fbln5 上调被葡萄糖激酶抑制剂、K 通道开放剂、钙通道阻滞剂和钙调神经磷酸酶抑制剂所抑制，而被双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）抑制剂 harmine 所增强。尽管在小鼠中敲除 Fbln5 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 Fbln5 过表达可增加 INS-1 大鼠胰岛细胞瘤中葡萄糖刺激的胰岛素分泌。由于胰岛 Fbln5 的表达受葡萄糖激酶/K 通道/钙调神经磷酸酶/活化 T 细胞核因子（NFAT）通路调控，该通路对β细胞功能的维持至关重要，因此有必要进一步研究 Fbln5 在胰岛中的功能。
