Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress

Free Radic Biol Med. 2009 Mar 15;46(6):783-90. doi: 10.1016/j.freeradbiomed.2008.11.026. Epub 2008 Dec 14.


Intermittent hypoxia (IH), such as occurs in sleep apnea, induces increased oxidative stress and is associated with altered glucose homeostasis. Because pancreatic beta cells are very sensitive to oxidative stress we tested whether they could be affected by IH. The effects of IH exposure (24 h/day, 5.7 and 21% O(2) alternation) in mice on beta-cell proliferation and beta-cell death were tested using Ki67 staining and TUNEL staining, respectively. To assess the role of oxidative stress in these processes, transgenic mice with beta-cell-specific overexpression of the antioxidant protein MnSOD were exposed to IH. After 4 days of IH exposure, beta-cell proliferation was increased almost fourfold. Coinciding with the increase in proliferation, the subcellular localization of the cell cycle regulator cyclin D2 was increased in the nucleus. In addition, beta-cell death was increased approximately fourfold. MnSOD transgene did not alter the effects of IH on beta-cell proliferation, but completely abrogated the IH effects on cell death. Thus, IH exposure that mimics sleep apnea can lead to increased beta-cell proliferation and cell death. Furthermore, the cell death response seems to be due to oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Death
  • Cell Nucleus / metabolism*
  • Cell Proliferation
  • Cyclin D2 / metabolism*
  • Hypoxia
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Ki-67 Antigen
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / physiology
  • Oxidative Stress
  • Reactive Oxygen Species
  • Sleep Apnea Syndromes / genetics*
  • Sleep Apnea Syndromes / pathology
  • Sleep Apnea Syndromes / physiopathology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*


  • Ccnd2 protein, mouse
  • Cyclin D2
  • Ki-67 Antigen
  • Reactive Oxygen Species
  • Superoxide Dismutase