title: Moderate hypoxia induces β-cell dysfunction with HIF-1-independent gene expression changes.
abstract: Pancreatic β-cell failure is central to the development and progression of type 2 diabetes. We recently demonstrated that β-cells become hypoxic under high glucose conditions due to increased oxygen consumption and that the pancreatic islets of diabetic mice but not those of control mice are moderately hypoxic. However, the impact of moderate hypoxia on β-cell number and function is unknown. In the present study, moderate hypoxia induced a hypoxic response in MIN6 cells, as evidenced by increased levels of HIF-1α protein and target genes. Under these conditions, a selective downregulation of Mafa, Pdx1, Slc2a2, Ndufa5, Kcnj11, Ins1, Wfs1, Foxa2, and Neurod1, which play important roles in β-cells, was also observed in both MIN6 cells and isolated pancreatic islets. Consistent with the altered expression of these genes, abnormal insulin secretion was detected in hypoxic MIN6 cells. Most of the hypoxia-induced gene downregulation in MIN6 cells was not affected by the suppression of HIF-1α, suggesting a HIF-1-independent mechanism. Moderate hypoxia also induced apoptosis in MIN6 cells. These results suggest that hypoxia is a novel stressor of β-cells and that hypoxic stress may play a role in the deterioration of β-cell function.
authors.affiliation: Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.affiliation: Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009245:NADH Dehydrogenase / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051273:Glucose Transporter Type 2; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D051473:Maf Transcription Factors, Large; D008565:Membrane Proteins; D009245:NADH Dehydrogenase; D024661:Potassium Channels, Inwardly Rectifying; D015534:Trans-Activators; D000099161:Kcnj11 Channel; C496503:Foxa2 protein, mouse; C497443:Hif1a protein, mouse; C514817:Ins1 protein, mouse; C485160:Mafa protein, mouse; C000592702:NDUFA5 protein, mouse; C501008:Neurod1 protein, mouse; C495682:Slc2a2 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C114987:wolframin protein