Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies

Abstract

Background and objectives: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM).

Methods: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections.

Results: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected.

Discussion: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.

Figure. Frequency of DM and Immunofluorescence Stainings on Pancreatic Tissue

(A) Frequency of diabetes mellitus is significantly elevated in patients seropositive for antiparanodal antibodies (33.3%) compared with seronegative patients (14.1%, p = 0.014) and with the general German population (9.9%, p < 0.001), especially in anti–contactin-1-seropositive patients (58.3% vs 14.1% in seronegative, p < 0.001 and 9.9% in the German population, p < 0.001). Significance levels are marked with asterisks: *p < 0.05, **p < 0.01, ***p < 0.001. (B) In seropositive patients not having received corticosteroid treatment within the last 28 days and who were therapy naive to rituximab, HbA1c levels (y-axis, %) were determined in 14 patients at the time point of serum withdrawal and correlated significantly with the autoantibody titer, displayed on a logarithmic scale (r = 0.58, p = 0.029). (C.a–l) Photomicrographs show human pancreatic normal tissue sections with nucleus staining (DAPI) shown in blue (C.a, C.d, C.g, and C.j) and double staining with synaptophysin as marker for the islets of Langerhans (displayed in green, C.b, C.e, C.h, and C.k) and serum or antiparanodal antibodies (displayed in magenta, C.c, C.f, C.i, and C.l). Serum of a patient with CIDP and DM type 1 with GAD antibodies binds to β cells in pancreatic islets of Langerhans (C.a–c), whereas serum of a patient with anti–contactin-1 antibodies (C.d–f) and commercial goat anti–contactin-1 (C.g–i) and commercial chicken anti–pan-neurofascin (C.j–l) do not show any binding. Photomicrographs of binding of the other patients' sera or commercial antibodies tested in the assay are not shown. Scale bar = 10 μm. CNTN = contactin-1; DAPI = 4′,6-diamidino-2-phenylindole; DM = diabetes mellitus; HbA1c = hemoglobin A1C.