Abstract
Diabetic polyneuropathy (DPN) and endothelial dysfunction are prevalent complications of diabetes mellitus. Currently, there are two non-invasive markers for endothelial dysfunction: flow-mediated dilation and reactive hyperaemia peripheral arterial tonometry (RH-PAT). However, the relationship between diabetic small fibre neuropathy and macroangiopathy remains obscure thus far. Corneal confocal microscopy (CCM) has emerged as a new diagnostic modality to assess DPN, especially of small fibre. To clarify the relationship between diabetic small fibre neuropathy and vascular dysfunction, we aimed to determine the functions of peripheral nerves and blood vessels through clinical tests such as nerve conduction study, coefficient of variation in the R-R interval, CCM, and RH-PAT in 82 patients with type 2 diabetes. Forty healthy control subjects were also included to study corneal nerve parameters. Correlational and multiple linear regression analyses were performed to determine the associations between neuropathy indices and markers for vascular functions. The results revealed that patients with type 2 diabetes had significantly lower values for most variables of CCM than healthy control subjects. RH-PAT solely remained as an explanatory variable significant in multiple regression analysis for several CCM parameters and vice versa. Other vascular markers had no significant multiple regression with any CCM parameters. In conclusion, endothelial dysfunction as revealed by impaired RH-PAT was significantly associated with CCM parameters in patients with type 2 diabetes. This association may indicate that small fibre neuropathy results from impaired endothelial dysfunction in type 2 diabetes. CCM parameters may be considered surrogate markers of autonomic nerve damage, which is related to diabetic endothelial dysfunction. This study is the first to report the relationship between corneal nerve parameter as small fibre neuropathy in patients with type 2 diabetes and RH-PAT as a marker of endothelial dysfunction.
Highlights
The pathophysiology and disease progression of diabetic polyneuropathy (DPN), which is the most frequent diabetic complication [1], remain unclarified as compared to those of other diabetic microvascular complications such as retinopathy or nephropathy
We reported that the cardiovascular ankle index (CAVI) has a significant relationship with the results of Nerve conduction study (NCS) and markers of large fibre neuropathy in patients with type 2 diabetes [12]
We investigated cross-sectionally the association of reactive hyperaemia peripheral arterial tonometry (RH-peripheral arterial tone (PAT)) and other physiological vascular markers with corneal nerve parameters, which were evaluated by confocal microscopy, and other neuropathy markers such as NCS
Summary
The pathophysiology and disease progression of diabetic polyneuropathy (DPN), which is the most frequent diabetic complication [1], remain unclarified as compared to those of other diabetic microvascular complications such as retinopathy or nephropathy. The reason why DPN has received inadequate attention, with exacerbated severity, is due to the lack of simple, objective measuring tools for the diagnosis and estimation of therapeutic effects. 70–90% of peripheral nerves are small fibres (mostly unmyelinated). Small unmyelinated C fibres convey warm and cold thermal perception. Various methods support the diagnosis of small fibre neuropathy. Physical signs such as the presence and distribution of sensory loss and pain, gait impairment, and dysautonomic symptoms and quantitative sensory testing were utilised. The gold standard for diagnosis is the estimation of intra-epidermal nerve fibre density (IENFD); the procedure is somewhat invasive and timeconsuming. In vivo corneal confocal microscopy (CCM) is used widely as a non-invasive and simple device because all corneal nerves consist of small C and A-d fibres. Several previous reports suggested that corneal nerve changes can enable the detection of diabetic autonomic neuropathy [4,5,6]
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