Abstract
ObjectivesThe progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy‐related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy.Patients and MethodsSural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM.ResultsSubjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g‐ratio versus subjects who remained NGT. At follow‐up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline.ConclusionsWe conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy.
Highlights
Diabetic neuropathy can affect 50% of patients with diabetes and is associated with increased morbidity and mortality (Wild, Roglic, Green, Sicree, & King, 2004)
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)
The seven subjects (1 normal glucose tolerance (NGT) + 6 IGT), who converted to T2DM, demonstrated a significant reduction in myelinated nerve fiber density (p < .02) and sural nerve amplitude (p < .02) and an increase in myelinated axon diameter (p < .03), indicating a loss of mostly smaller myelinated axons, but no change in unmyelinated fibers versus baseline (Table 4)
Summary
Diabetic neuropathy can affect 50% of patients with diabetes and is associated with increased morbidity and mortality (Wild, Roglic, Green, Sicree, & King, 2004). An array of factors, such as dysfunction of mitochondria and endoplasmic reticulum, hypercholesterolemia, endothelial dysfunction, and ischemia/hypoxia, are considered to play an important role in the development of diabetic neuropathy (Callaghan et al, 2012; Cashman & Höke, 2015; Feldman, Nave, Jensen, & Bennett, 2017; Gonçalves et al, 2017). 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, 1989, 2005; Thomas 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). We have recently shown that subjects with IGT may already have a significant small fiber neuropathy (Asghar et al, 2014) and that subjects with IGT who develop T2DM have a greater degree of small fiber pathology (Azmi et al, 2015)
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