title: Chronic intermittent hypoxia increases β cell mass and activates the mammalian target of rapamycin/hypoxia inducible factor 1/vascular endothelial growth factor A pathway in mice pancreatic islet.
abstract: BACKGROUND
  Growing evidence from population and clinic based studies showed that obstructive sleep apnea (OSA) and its characterizing chronic intermittent hypoxia (IH) were independently associated with the development of type 2 diabetes mellitus. However, the pathogenesis by which OSA induces glucose metabolic disorders is not clear. We determined changes in pancreatic β cell mass and the mammalian target of rapamycin (mTOR)/hypoxia inducible factor 1 (HIF-1)/vascular endothelial growth factor A (VEGF-A) pathway following IH exposure.
  
  
  METHODS
  A controlled gas delivery system regulated the flow of nitrogen and oxygen into a customized cage housing mice during the experiment. Twenty-four male wild C57BL/6J mice were either exposed to IH (n = 12) or intermittent air as a control (n = 12) for 56 days. Mice were anaesthetized and sacrificed after exposure, pancreas samples were dissected for immunofluorescent staining. Insulin and DAPI staining labelled islet β cells. Insulin positive area and β cell number per islet were measured. P-S6, HIF-1α and VEGF-A staining were performed to detect the activation of mTOR/HIF-1/VEGF-A pathway.
  
  
  RESULTS
  After eight weeks of IH exposure, insulin positive area increased by an average of 18.5% (P < 0.05). The β cell number per islet increased (92 vs. 55, respectively for IH and the control groups, P < 0.05) with no change in the size of individual β cells. Islet expression of HIF-1α and VEGF-A were higher in IH group than control group, and percentage of p-S6 positive β cell also increased after IH exposure (16.8% vs. 4.6% respectively for IH and the control groups, P < 0.05).
  
  
  CONCLUSIONS
  The number of pancreatic β cells increased as did the activity of the mTOR/HIF-1/VEGF-A pathway after exposure to IH.
authors.affiliation: Department of Respiratory Medicine, Shanghai Ruijin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Chen-Juan
authors.initials: CJ
authors.lastname: Gu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Li
mesh_terms: D000818:Animals; D000860:Hypoxia / Q000473:pathology*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases