An increased skin microvessel density is associated with neurovascular complications in type 1 diabetes mellitus

Abstract

The aim of this study was to assess the blood vessel density and maturity in the skin of adults with type 1 diabetes in relation to the presence of late neurovascular complications. We included 148 patients (87 men) with a median (interquartile range) age of 41 (31–49) and median diabetes duration of 21 (17–30) years. Microvessel (CD133, CD34, CD31 and von Willebrand factor) markers were evaluated by indirect immunohistochemistry assay in material from a skin biopsy. Diabetic retinopathy was diagnosed using direct ophthalmoscopy, and diabetic kidney disease was estimated in people with increased albuminuria and a 10-year duration of diabetes or evidence of diabetic retinopathy . Diabetic peripheral neuropathy diagnosis was based on Toronto definition, cardiac autonomic neuropathy on validated ProSciCard III program. Microvessel density, assessed by CD34 and CD133, was significantly higher in patients with cardiac autonomic neuropathy [160 (125–175) vs 121 (100–154)/1 mm2, p = 0.001 and 92 (83–104) vs 79 (63–92)/1 mm2, p = 0.007, respectively] and CD34 in patients with diabetic peripheral neuropathy [135 (106–168) vs 121 (95–145)/1 mm2, p = 0.018], as compared with subjects without complications. In multivariate logistic regression, density of CD34 and CD133 positive vessels was associated with presence of cardiac autonomic neuropathy [odds ratio 1.016 (95% confidence interval: 1.002–1.029), p = 0.019 and odds ratio 1.037 (95% confidence interval: 1.008–1.067), p = 0.011, respectively]. It was independent from age, sex, diabetes duration, smoking status, body mass index and HbA1c value. Density of CD34 positive vessels was also associated with diabetic peripheral neuropathy, independently from sex and diabetes duration [odds ratio 1.009 (95% confidence interval: 1.001–1.020), p = 0.037]. Skin microvessel density is increased in adults with clinical evidence of neurovascular complications of type 1 diabetes. This is associated with predominance of the vessels of low maturity.

Disturbances in angiogenesis and vascular maturation in the skin are associated with diabetic kidney disease in type 1 diabetes

“…Previously, we have observed that MVD, assessed by CD34 (a marker of "late" EPCs) and CD133 (a marker of early EPCs), were significantly higher in patients with cardiac autonomic neuropathy Note: data are presented as median (interquartile range) or N (%); p = 0.33 for comparison vWF+ MVD between groups with CKD stages 1,2, and 3a; p = 0.056 for comparison vWF+ MVD between groups with CKD stages 1,2, and 3 (combined); Kruskal-Wallis test; N -number of patients; eGFR -estimated glomerular filtration rate; MDRD -Modification of Diet in Renal Disease (CAN). Also, CD34 MVD was higher in patients with diabetic peripheral neuropathy (DPN), as compared to subjects without complications [16]. These results support the concept that angiogenic processes are involved in the pathogenesis of neuropathy and confirm the neurovascular nature of chronic diabetes complications.…”

Optical coherence tomography: a novel imaging approach to visualize and quantify cutaneous microvascular structure and function in patients with diabetes

“…Another promising future opportunity is the combination of OCT visualization and quantification of in vivo functional responses alongside skin biopsy techniques. In recent studies, biopsies performed in the lower leg have revealed lower 28 and higher 29 microvascular density in diabetic versus control subjects, perhaps depending on the disease type and severity.…”

Redefining distal symmetrical polyneuropathy features in type 1 diabetes: a systematic review

“…Only two cross-sectional prospective studies (8.7%) used Toronto consensus criteria, reporting a prevalence of 14% and 23%, respectively [18,19]. Three studies (12.5%), including between 74 and 126 patients, used ADA criteria without any diagnostic test confirmation and reported a prevalence between 5 and 25.4% [20][21][22].…”

“…oxide synthase (eNOS) activity, with resulting hindrance to endoneurial blood flow [104]. All these mechanisms, leading to mitochondrial dysfunction and DNA damage with recruitment of inflammatory mediators and cellular death, converge in the clinical picture of diabetic neuropathy [103], affecting not only neurons, but also glial cells and endothelial ones, with microcirculatory dysfunction [18,40]. Even Schwann cells are affected and demyelinating features may be present in most severe cases, despite diabetic neuropathy being considered a primarily axonal neuropathy [103].…”