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

Abstract

Background: Obstructive 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).

Methods: A 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.

Results: Skin 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).

Conclusions: OSA 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.

Keywords: Foot ulceration; Intra-epidermal nerve fiber density; Neuropathy; PARP; Sleep apnea; Type 2 diabetes.