Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2014, Vol.78 (5), p.843-850
• Main Authors: Matsunaga, Tetsuro, Li, Shiho, Adachi, Tetsuya, Joo, Erina, Gu, Ning, Yamazaki, Hanae, Yasuda, Koichiro, Kondoh, Takashi, Tsuda, Kinsuke
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases - genetics; Animals; Cell Line; Dose-Response Relationship, Drug; Drosophila Proteins - genetics; Gene Expression Regulation - drug effects; Glucokinase - genetics; Glucose - adverse effects; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 2 - genetics; glucotoxicity; Homeodomain Proteins - genetics; hyperoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor 1α; INS-1 cells; insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Ion Channels - genetics; Mitochondrial Proteins - genetics; Nitroimidazoles - pharmacology; Oxygen - metabolism; Rats; Trans-Activators - genetics; Uncoupling Protein 2
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1080/09168451.2014.905175

Chronic hyperglycemia has deleterious effects on pancreatic β-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 β cells, and whether hyperoxia (35% O 2 ) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3 mm, 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 1α (HIF-1α) 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-1α activation. These results suggest that glucotoxicity may cause β-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced β-cell dysfunction and improve insulin secretion. Chronic high glucose attenuated insulin secretion and increased intracellular pimonidazole-protein adducts, a marker for hypoxia, in INS-1 β cells. These changes associated were effectively reversed by treatment with hyperoxia (35 % O 2 atmosphere).