Hyperoxia Reverses Glucotoxicity-Induced Inhibition Of Insulin Secretion In Rat Ins-1 Beta Cells

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.