Inflammation, insulin resistance (IR) , and deficit of retrograde axonal transport (RAT) are implicated in the pathogenesis of diabetic polyneuropathy (DPN) . Pro-inflammatory macrophage (M1) skewed by diabetic insults causes IR in adipose tissue. The activation of Advanced Glycation End products (AGEs) - Receptor for AGEs (RAGE) signaling is involved in the macrophage polarization into M1, while its contribution to the deficit of RAT in DPN is still unclear. In this study, we investigated the implication of M1-related inflammation to RAT deficit in sensory neurons. We evaluated the activation of macrophage cell line RAW 264.7 (RAW) and neurons isolated from dorsal root ganglia (DRG) of C57BL/6 mice stimulated by 200 μg/ml of AGE. A DRG neurons-RAW co-culture system was established by seeding RAW onto DRG neurons. After 12h co-culturing, we added AGE to the co-culture and stimulated RAW. A DRG neuronal mono-culture was treated with 500 nM of insulin receptor antagonist (BMS-754807) , and 20 ng/ml of TNF-α with/without 50 nM JNK inhibitor (SP600125) . Axonal transport was visualized by Lysotracker and captured by time-lapse microscopy. The movements were quantified on kymographs generated from 100 μm axonal segments. AGE induced the M1 phenotype in RAW with elevated expressions of iNOS and TNF-α mRNA, while no effects on DRG neuron were identified. In the co-culture, the frequency of RAT (RAT%) was significantly reduced when RAW was stimulated by AGE compared to naive RAW (p < 0.001) . In the mono-culture, RAT% was significantly reduced when neurons were treated with BMS-7548 and TNFα (vs. control, both p < 0.001) . TNFα stimulation also increased the phosphorylation of JNK in the axons, a major target of TNFα, which was confirmed by immunofluorescence. The reduction of RAT% by TNFα was rescued by SP600125. In summary, RAT could be impaired by TNF-α and IR, which suggests inflammation induced by M1 in SN can attenuate RAT, which contributes to the DPN pathology. Disclosure S.Osonoi: None. H.Mizukami: None. S.Ogasawara: None. K.Kudoh: None. M.Daimon: None. S.Yagihashi: None. Funding Japan Society for the Promotion of Science (18K16220)
Small fiber neuropathy (SFN) manifests from the early stages of diabetic polyneuropathy. Changes in the oral and intestinal bacterial flora are known to be associated with the onset and progression of diabetes and its complications. However, correlation between SFN and each bacterial flora has not yet been investigated. In the 2018 Iwaki health promotion project, which is a local health promotion study in Aomori prefecture, 1037 participants (431 males and 6females including 814 non-glucose metabolism disorders, 143 fasting hyperglycemia (IFG) , and 80 type 2 diabetic cases (DM) , were evaluated. SFN was evaluated by the pain threshold evoked by intraepidermal electrical stimulation (PINT) . A PINT value of 0.or less was designated as Pint-L, and otherwise was designated as Pint-H. DNA was isolated from saliva and feces and relative bacterial abundance was determined with a next-generation sequencer. Bacteria that account for 1% or more of all bacteria were examined. PINT was significantly increased in IFG (0.12 ± 0.11mA) and DM (0.15 ± 0.13mA) compared to healthy subjects (0.± 0.08mA) (p<0.vs. IFG, p <0.vs. DM) . No significant difference was found depending on the PINT value in the bacteria flora of oral cavity. There were significant differences of gut bacterial flor in α and β-diversity (p<0.05) and principal component analysis (p <0.01) depending on the PINT value. The genus Bacteroides was significantly higher in PINT-H than in PINT-L (p<0.01) . After IFG and DM cases were excluded, a significant difference was maintained. The amount of bacteroides was significantly correlated with age, abdominal circumference, fasting blood glucose, HbA1c (p<0.001) , BMI and PINT value (p <0.05) . In the multiple regression analysis adjusted for these factors, PINT was significantly correlated with the amount of Bacteroides (β = -0.089, p = 0.026) . Our results suggest that the gut Bacteroides may correlate with SFN. The involvement of deterioration of glucose metabolism may not be high in this correlation. Disclosure K.Kudoh: None. Y.Takeuchi: None. S.Osonoi: None. T.Sasaki: None. S.Ogasawara: None. S.Yagihashi: None. H.Mizukami: None.
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