The relationship between obstructive sleep apnea and intra-epidermal nerve fiber density, PARP activation and foot ulceration in patients with type 2 diabetes

Abstract

BackgroundObstructive sleep apnea (OSA) is associated with increased nitrosative stress, endothelial dysfunction, and peripheral neuropathy in patients with type 2 diabetes. We hypothesized that OSA is associated with Poly ADP ribose polymerase (PARP) activation, lower intra-epidermal nerve fiber density (IENFD), and diabetic foot ulceration (DFU). MethodsA cross-sectional study of adults with type 2 diabetes recruited from a secondary care hospital in the UK. OSA was assessed by multi-channel home-based cardio-respiratory device (Alice PDX, Philips Respironics). DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). IENFD and % PAR stained nuclei were assessed using immunohistochemistry staining on skin biopsies. DFU was assessed based on MNSI. ResultsSkin biopsies and DFU data were available from 52 and 234 patients respectively. OSA was associated with lower IENFD (12.75±1.93 vs. 10.55±1.62 vs. 9.42±1.16 fibers/mm of epidermis for no OSA, mild OSA and moderate to severe OSA respectively, p<0.001). Following adjustment, mild (B=−2.19, p=0.002) and moderate to severe OSA (B=−3.45, p<0.001) were independently associated with IENFD. The apnea hypopnea index (AHI) was associated with IENFD following adjustment (B=−2.45, p<0.001). AHI was associated with percentage of PAR stained nuclei following adjustment (B=13.67, p=0.025). DFU prevalence was greater in patients with OSA (7.1% vs. 28.1% vs. 26.2% for patients with no OSA, mild OSA and moderate to severe OSA respectively, p=0.001). Following adjustment, OSA was associated with DFU (OR 3.34, 95% CI 1.19–9.38, p=0.022). ConclusionsOSA is associated with lower IENFD, PARP activation and DFU in patients with type 2 diabetes. Our findings suggest that OSA is associated with small fiber neuropathy. PARP activation is a potential mechanisms linking OSA to DPN and endothelial dysfunction in patients with type 2 diabetes. Whether OSA treatment will have a favorable impact on these parameters and DFU requires interventional studies.