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



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.



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).



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.
Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Quratul-Ain Altaf
QA
Altaf
Department of Respiratory Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
Asad
A
Ali
Department of Diabetes and Endocrinology, Derby Teaching Hospitals NHS Foundation Trust, Derby, UK; Warwick Medical School, University of Warwick, Coventry, UK.
Milan K
MK
Piya
Independent Epidemiology and Statistical Consultant, Epidemiology, Research Design and Statistical Consulting (ERDASC), Leicestershire, UK.
Neil T
NT
Raymond
Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. Electronic address: abd.tahrani@nhs.net.
Abd A
AA
Tahrani
D000368:Aged; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D017719:Diabetic Foot / Q000453:epidemiology*; D004817:Epidermis / Q000294:innervation*; D005260:Female; D006801:Humans; D008297:Male; D008824:Michigan; D008875:Middle Aged; D009412:Nerve Fibers / Q000502:physiology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D020181:Sleep Apnea, Obstructive / Q000453:epidemiology*
D000071137:Poly (ADP-Ribose) Polymerase-1
Foot ulceration; Intra-epidermal nerve fiber density; Neuropathy; PARP; Sleep apnea; Type 2 diabetes