4.6 Article

Moderate Hypoxia Induces β-Cell Dysfunction with HIF-1-Independent Gene Expression Changes

Journal

PLOS ONE
Volume 9, Issue 12, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0114868

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Funding

  1. Banyu Life Science Foundation International
  2. Takeda Science Foundation
  3. Novo Nordisk Insulin Research Foundation
  4. Grants-in-Aid for Scientific Research [26111001] Funding Source: KAKEN

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Pancreatic beta-cell failure is central to the development and progression of type 2 diabetes. We recently demonstrated that beta-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 beta-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-1 alpha 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 beta-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-1 alpha, suggesting a HIF-1-independent mechanism. Moderate hypoxia also induced apoptosis in MIN6 cells. These results suggest that hypoxia is a novel stressor of beta-cells and that hypoxic stress may play a role in the deterioration of beta-cell function.

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