Impaired Glycemia and Diabetic Polyneuropathy

Clark, Vicki M.; Overland, Carol J.; Davies, Julian; Pach, John M.; Dyck, Peter J.; Klein, Christopher J.; Rizza, Robert A.; Melton, L. Joseph; Carter, Rickey E.; Klein, Ronald; Litchy, William J.

doi:10.2337/dc11-1421

Cited by 86 publications

(96 citation statements)

References 41 publications

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“…A peripheral axonal neuropathy affecting small fibers in subjects with IGT has been described in some, but not other (Dyck et al, 2012;Eriksson et al, 1994), studies. We have previously demonstrated a significant small fiber neuropathy in skin biopsies and using corneal confocal microscopy in subjects with IGT (Asghar et al, 2014), particularly those who develop T2DM (Azmi et al, 2015).…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2017

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Objectives: The 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 autophagyrelated 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 Methods:Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM.Results: Subjects 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. Conclusions:We 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. K E Y W O R D Sautophagy, diabetes, endoneurial capillary, impaired glucose tolerance, morphometry, peripheral neuropathy

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Section: Discussionmentioning

confidence: 93%

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

et al. 2017

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“…We have previously provided reference values for S 2 NC, S 4 NC, S 5 NC, and S 6 NC, but other nd composite scores can be derived. 34 Attributes of nerve conduction provide an objective and reliable indication of large-fiber function and dysfunction but do not provide direct information about small-fiber function or dysfunction. To provide an objective and quantitative indication of both large and small sensory fiber involvement, we combined a composite measure of large-fiber function, i.e., S 5 NC nds, and a measure of small fibers (ENFs/mm nds), and corrected both measures for applicable variables of age, gender, and physical characteristics.…”

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confidence: 99%

Epidermal nerve fibers

et al. 2012

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Objectives: Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm. Methods:The 95% CI studies were performed on 1, 1-2, 1-3 ---1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus.Results: Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 ---1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality.Conclusion: Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials. Neurology Enumeration of nerve endings in skin has been used to study differences among species, 1,2 development, maturation and aging, 3,4 and disease. 5,6 Light microscopic analysis of immune-stained intraepidermal nerve fibers (ENFs) and reference values were introduced to serve as objective and spatial indications of painful and small-fiber sensory polyneuropathy, "possibly useful for therapeutic trials." [7][8][9] The technique of biopsy was found to be acceptable to patients, and the estimation of ENFs/mm had high intraobserver and interobserver reproducibility.8 A somewhat different approach using punch skin biopsy, a blister technique with immunofluorescence and confocal microscopy, was also described (reviewed in Kennedy and Wendelschafer-Crabb 10 and Kennedy et al. 11). A series of reports showed the value of ENFs/mm in the diagnosis of painful small-fiber sensory polyneuropathy, especially in patients with few or no neurologic signs or test abnormalities.

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“…[30] While some earlier studies have also reported similar findings, [31] these have not been confirmed by others. [32], [33] We noted a prevalence of albuminuria of 20% among newly diagnosed T2DM.…”

Section: Resultsmentioning

confidence: 99%