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).

Conclusion: The number of pancreatic β cells increased as did the activity of the mTOR/HIF-1/VEGF-A pathway after exposure to IH.