title: Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells.
abstract: 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% O2) 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.
authors.affiliation: a Faculty of Health and Living Sciences Education , Naruto University of Education , Naruto , Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Shiho
authors.initials: S
authors.lastname: Li
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Erina
authors.initials: E
authors.lastname: Joo
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.forename: Hanae
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yasuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondoh
authors.forename: Kinsuke
authors.initials: K
authors.lastname: Tsuda
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics; D005947:Glucose / Q000009:adverse effects*; D051272:Glucose Transporter Type 1 / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D009593:Nitroimidazoles / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000235:genetics; D000071246:Uncoupling Protein 2
chemical_list: D029721:Drosophila Proteins; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; C497444:Hif1a protein, rat; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009593:Nitroimidazoles; D015534:Trans-Activators; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C084010:pancreatic and duodenal homeobox 1 protein; C033815:pimonidazole; D005941:Glucokinase; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578560:Pdk1 protein, Drosophila; D005947:Glucose; D010100:Oxygen
keywords: INS-1 cells; glucotoxicity; hyperoxia; hypoxia-inducible factor 1α; insulin