Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Maryland, Baltimore, Maryland, United States of America.
PLoS One. 2014 Feb 25;9(2):e90192. doi: 10.1371/journal.pone.0090192. eCollection 2014.
Without zinc, pancreatic beta cells cannot either assemble insulin molecules or precipitate insulin crystals; thus, a lack of zinc concentration in the beta cells would result in a decreased insulin production. ZIP8 is one of the zinc uptake transporters involved in zinc influx into the cytosol of beta cells. Thus, if ZIP8 is down-regulated, a decreased insulin production would result. We assumed that intermittent hypoxic exposure to the beta cells may result in a decreased production of insulin due to a lack of zinc. To test this hypothesis we harvested pancreatic islets from the rats conditioned under intermittent hypoxia (IH) (fluctuating between 20.5% and 10% every 4 min for 1 h) and compared the results with those from control animals and islets. We also compared their insulin and glucose homeostasis using glucose tolerance tests (GTT) after 3 weeks. GTT results show a significant delay (P<0.05) in recovery of the blood glucose level in IH treated pups. ZIP8 expression in the beta cell membrane was down-regulated. The zinc concentration in the cell as well as insulin production was significantly decreased in the islets harvested from IH animals. However, mRNA for insulin and C-peptide/insulin protein levels in the total cell lysates remained the same as those of controls. When we treated the beta cells using siRNA mediated ZIP8, we observed the commensurate results from the IH-treated islets. We conclude that a transient IH exposure could knockdown ZIP8 transporters at mRNA as well as protein levels in the beta cells, which would decrease the level of blood insulin. However, the transcriptional activity of insulin remains the same. We conclude that the precipitation process of insulin crystal may be disturbed by a lack of zinc in the cytosol that is modulated by mainly ZIP8 after IH exposure.
在缺锌的情况下，胰腺β细胞既不能组装胰岛素分子，也不能沉淀胰岛素晶体；因此，β细胞中锌浓度的缺乏会导致胰岛素产生减少。ZIP8 是参与锌流入β细胞胞质溶胶的锌摄取转运体之一。因此，如果 ZIP8 下调，胰岛素的产生就会减少。我们假设β细胞间歇性缺氧暴露可能会由于缺锌而导致胰岛素产生减少。为了验证这一假设，我们从接受间歇性缺氧（IH）条件处理的大鼠的胰岛中提取了胰腺胰岛（波动范围为每 4 分钟从 20.5%到 10%，持续 1 小时），并将结果与对照组动物和胰岛进行了比较。我们还比较了它们在 3 周后进行葡萄糖耐量试验（GTT）后的胰岛素和葡萄糖稳态。GTT 结果显示，IH 处理的幼鼠血糖水平的恢复明显延迟（P<0.05）。β细胞膜上的 ZIP8 表达下调。从 IH 动物胰岛中提取的细胞中的锌浓度以及胰岛素产量显著降低。然而，总细胞裂解物中的胰岛素和 C 肽/胰岛素蛋白水平的 mRNA 与对照组相同。当我们使用 siRNA 介导的 ZIP8 处理β细胞时，我们观察到与 IH 处理的胰岛相同的结果。我们得出结论，短暂的 IH 暴露可以在 mRNA 和蛋白水平上使β细胞中的 ZIP8 转运体失活，从而降低血液胰岛素水平。然而，胰岛素的转录活性保持不变。我们得出结论，胰岛素晶体的沉淀过程可能会因细胞溶胶中锌的缺乏而受到干扰，而这种干扰主要是由 IH 暴露后主要的 ZIP8 调节的。
