Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy

Abstract

Clinical, electrophysiological and ultrastructural morphometric observations were made in 5 diabetic non-neuropathic patients, 5 diabetic patients with mild neuropathy and 11 diabetic patients with severe neuropathy. Capillary abnormalities were assessed in simultaneous nerve, muscle and skin biopsies and compared with results from 6 age-matched, non-diabetic control subjects. Nerve capillaries demonstrated markedly greater pathology than skin and muscle capillaries. Endoneurial capillary density was significantly reduced in severely neuropathic diabetic patients (p less than 0.01) when compared with control subjects. Capillary basement membrane (p less than 0.002), endothelial cell (p less than 0.003) and total diffusion barrier (endothelial cell, pericyte, basement membrane) (p less than 0.001) thickness were significantly increased, and oxygen diffusing capacity was significantly reduced (p less than 0.001) in the nerves of patients with severe diabetic neuropathy when compared to control subjects. Endothelial cell profile number and luminal perimeter were significantly increased in asymptomatic (p less than 0.01), (p less than 0.05) and severely neuropathic (p less than 0.001), (p less than 0.05) diabetic patients respectively. However, endothelial cell outer perimeter, a measure of capillary size, showed no significant increase in diabetic patients when compared with control subjects. An association was observed between neurophysiological and neuropathological measures of neuropathic severity. There was no significant correlation between the duration of diabetes and HbA1 levels with capillary pathology or with neuropathic severity. Very few abnormalities of muscle and skin correlated with neuropathic severity. However, all measures of nerve capillary pathology correlated significantly with neurophysiological and neuropathological measures of neuropathic severity.

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

“…We have previously shown a significant microangiopathy evidenced by basement membrane thickening, reduction in luminal size, and endothelial cell hyperplasia in patients with initially minimal but progressive diabetic neuropathy (Malik et al, 2005). In patients with T2DM, we show basement membrane thickening and endothelial cell hyperplasia and hypertrophy as also reported by others (Giannini & Dyck, 1995;Malik et al, 1989Malik et al, , 2005Thrainsdottir et al, 2003;Yasuda & Dyck, 1987) without a reduction in luminal area which agrees with some (Giannini & Dyck, 1995), but not other (Dyck et al, 1985;Malik et al, 2005) studies. In the present study, in patients with T2DM, there were no evidence of microangiopathy at baseline but it developed over 11 years as a consequence of hyperglycemia and other cardiovascular risk factors (Calabek, Callaghan, & Feldman, 2014;Callaghan, Cheng, Stables, Smith, & Feldman, 2012;.…”

“…Vessels located in the perineurium and those with a major to minor axis ratio greater than 3:1 were excluded. Quantification was undertaken using our previously established morphometric techniques (Malik et al, 1989). The lumen area was calculated by tracing the inner endothelial cell border.…”

“…Pathological studies of sural nerve biopsies from patients with diabetic neuropathy typically demonstrate axonal atrophy, demyelination, axonal degeneration with regeneration, and microangiopathy (Biessels et al, 2014;Malik et al, 1989Malik et al, , 2005Thomas et al, 1996). We have previously shown that sural nerve endoneurial capillary density was increased and luminal area was decreased in subjects with impaired glucose tolerance (IGT) who progressed to type 2 diabetes (T2DM) (Thrainsdottir, Malik, & Dahlin, 2003).…”

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

“…Each fascicle was photographed at a total magnifi-cation of 400 times using a Vickers light microscope and camera; light micrograph montages were prepared of all fascicles from each biopsy. An image analysis cursor was used to trace the fascicular area, and the endoneurial capillaries and myelinated fibres were counted directly, enabling an assessment of mean fascicular area, endoneurial capillary density and myelinated fibre density [12].…”

“…Detailed neurophysiological studies in diabetic patients have shown that demyelination precedes axonal loss and that the latter may be responsible for the symptoms [8]. Whilst studies in patients with established neuropathy demonstrate a combination of demyelination and axonal degeneration of myelinated fibres and degeneration with regeneration of unmyelinated fibres [9][10][11] and endoneurial microangiopathy [12][13][14][15], the early pathological features of patients with diabetic neuropathy are not clearly defined.…”