Cutaneous Structural and Biochemical Correlates of Foot Complications in High-Risk Diabetes

Abstract

OBJECTIVEImpairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications.RESEARCH DESIGN AND METHODSA total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity.RESULTSMNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects.CONCLUSIONSIncreased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.

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

“…IENFD was assessed as we described previously (Tahrani et al, 2012b) and recommended by others (Lauria et al, 2010). Four randomly selected 50 µm sections were immunohistochemically stained using a free floating protocol with rabbit anti-human polyclonal PGP9.5 antibody (Biogenesis 1:1200).…”

“…PARP activity was measured using immunohistochemical method that quantifies the accumulation of PAR, the product of the PARP activation (Obrosova et al, 2004;Szabó et al, 2002). PAR was assessed as we described previously (Tahrani et al, 2012b). Paraffin sections (4µm) were dewaxed and endogenous peroxidases removed and blocked.…”

“…Hence, we hypothesized that OSA is associated with PARP activation in patients with Type 2 diabetes which can mediate the relationship between OSA and nitrosative stress and endothelial dysfunction, which we described previously (Tahrani et al, 2012a). PARP activation and oxidative stress have also been shown to play an important role in the pathogenesis of diabetic foot ulceration (DFU) (Tahrani et al, 2012b). Based on the association between OSA and DPN, abnormal 10g monofilament, oxidative and nitrosative stress and possibly PARP activation, we hypothesized that OSA is associated with DFU in patients with Type 2 diabetes.…”

Histomorphological and biochemical properties of plantar soft tissue in diabetes

“…These include alterations to the soft and hard tissue, nerve function, vascular structure, immunology, wound healing and plantar pressure [10–12]. Although the biochemistry of a number of tissues taken from persons with diabetes has been evaluated [9], the biochemistry of diabetic plantar soft tissue has been limited [13]. …”

Optical and structural properties of biological tissues under diabetes mellitus

“…The contradiction of results could be also due to the use of different models of diabetes mellitus. The change of collagen distribution in dermis was observed by means of histology and microscopy in diabetic patients with complications, in contrast to those having no complications [177]. The inconsistent results require checking or specifying the features of the experiment that could cause the contradictions.…”