Moderate hypoxia induces β-cell dysfunction with HIF-1-independent gene expression changes

PLoS One. 2014 Dec 12;9(12):e114868. doi: 10.1371/journal.pone.0114868. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • Cell Hypoxia / physiology*
  • Cell Line, Tumor
  • Gene Expression Regulation / physiology*
  • Glucose Transporter Type 2 / metabolism
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Homeodomain Proteins / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / pathology*
  • Maf Transcription Factors, Large / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NADH Dehydrogenase / metabolism
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Real-Time Polymerase Chain Reaction
  • Trans-Activators / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Foxa2 protein, mouse
  • Glucose Transporter Type 2
  • Hif1a protein, mouse
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ins1 protein, mouse
  • Insulin
  • Kir6.2 channel
  • Maf Transcription Factors, Large
  • Mafa protein, mouse
  • Membrane Proteins
  • NDUFA5 protein, mouse
  • Neurod1 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Slc2a2 protein, mouse
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • wolframin protein
  • Hepatocyte Nuclear Factor 3-beta
  • NADH Dehydrogenase

Grants and funding

This work was supported by a Grant-in-Aid for Young Scientists (B), a Grant-in-Aid for Scientific Research (B), a grant from Banyu Life Science Foundation International, a grant from Takeda Science Foundation, and a grant from Novo Nordisk Insulin Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.