Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells
Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells
复制标题
DOI：
10.1080/09168451.2014.905175
复制
发表时间：
2014-05-01
影响因子：
1.6
通讯作者：
Tsuda, Kinsuke
中科院分区：
文献类型：
--
作者：
Matsunaga, Tetsuro;Li, Shiho;Tsuda, Kinsuke
慢性高血糖症对胰腺β细胞功能具有有害影响，这一过程称为葡萄糖毒性。本研究检测了慢性高糖（CHG）是否诱导大鼠INS-1 β细胞的细胞缺氧，以及高氧（35%O-2）是否可以逆转葡萄糖毒性诱导的胰岛素分泌抑制。CHG（33.3mM，96 h）减少胰岛素分泌，下调胰岛素和胰腺十二指肠同源盒因子1基因表达。CHG还增加细胞内的pimonidazole蛋白加合物，缺氧的标志物。CHG还增强缺氧诱导因子1 α（HIF-1 α）蛋白表达及其DNA结合活性，伴随着葡萄糖转运蛋白2（GLUT 2）、葡萄糖激酶和解偶联蛋白-2的mRNA表达降低以及GLUT 1和丙酮酸脱氢酶激酶1的mRNA表达增加。高氧可恢复胰岛素分泌和GLUT 2以外基因表达的下降，并抑制细胞内缺氧和HIF-1a活化。这些结果表明，葡萄糖毒性可能导致β细胞缺氧。高氧可预防葡萄糖毒性诱导的β细胞功能障碍并改善胰岛素分泌。
Chronic hyperglycemia has deleterious effects on pancreatic beta-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 beta cells, and whether hyperoxia (35% O-2) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3mM, 96 h) reduced insulin secretion, and down-regulated insulin and pancreatic duodenal homeobox factor 1 gene expression. CHG also increased intracellular pimonidazole-protein adducts, a marker for hypoxia. CHG also enhanced hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein expression and its DNA-binding activity, which was accompanied by a decrease in mRNA expression of glucose transporter 2 (GLUT2), glucokinase and uncoupling protein-2 and an increase in mRNA expression of GLUT1 and pyruvate dehydrogenase kinase 1. Hyperoxia restored the decrease in insulin secretion and the gene expression except for GLUT2, and suppressed intracellular hypoxia and HIF-1a activation. These results suggest that glucotoxicity may cause beta-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced beta-cell dysfunction and improve insulin secretion.