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Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 ( = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease.

To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator. RESEARCH DESIGN AND METHODS This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations. RESULTS After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor-related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker. CONCLUSIONS General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association.

Dermal nerve fibre regeneration is enhanced in DSPN, particularly in DSPN+p, and increases with advancing intraepidermal nerve fibre loss. These data suggest that, despite progressive epidermal fibre loss, dermal nerve repair is preserved, particularly in DSPN+p, but fails to adequately counteract epidermal neurodegenerative processes.

Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in a-subunits of voltage-gated sodium channels (Na v s) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Na v s could expand the spectrum of patients with Na v-related peripheral neuropathies. The auxiliary sodium channel b-subunits (b1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na v. Mutations in b-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in b-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel a-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the b2-subunit. Functional analysis using current-clamp revealed that the b2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the b2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Na v 1.7 fast inactivation and reduced use-dependent inhibition of the Na v 1.7 channel.

Background: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity. Objectives: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity. Methods: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62–81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006–2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013–2014). Associations of annual average air pollutant concentrations at participants’ residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders. Results: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, , , , and ) and gaseous ( , ) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); ]. With the exception of , corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with [e.g., for PNC, (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); ]. Discussion: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311

: The various manifestations of diabetic neuropathy including distal symmetric sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) are among to the most prevalent chronic complications of diabetes. Major clinical complications of diabetic neuropathies such as neuropathic pain, chronic foot ulcers, and orthostatic hypotension are associated with considerable morbidity, increased mortality, and diminished quality of life. Despite the substantial individual and socioeconomic burden, the strategies to diagnose and treat diabetic neuropathies remain insufficient. This review provides an overview on the current clinical aspects and recent advances in exploring local and systemic biomarkers of both DSPN and CAN assessed in human studies (such as biomarkers of inflammation and oxidative stress) to better understand the underlying pathophysiology and to improve early detection. Current therapeutic options for DSPN are (I) causal treatment including lifestyle modification, optimal glycemic control, and multifactorial risk intervention; (II) pharmacotherapy derived from pathogenetic concepts; and (III) analgesic treatment against neuropathic pain. Recent advances in each category are discussed including non-pharmacological approaches such as electrical stimulation. Finally, the current therapeutic options for cardiovascular autonomic complications are provided. These insights should contribute to a broader understanding of the various manifestations of diabetic neuropathies from both the research and clinical perspectives.