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Pathophysiology/complications
Lipopolysaccharide-binding protein is a distinctive biomarker of abnormal pain threshold in the general Japanese population
  1. Kazuhiro Kudoh1,
  2. Hiroki Mizukami1,
  3. Chieko Itabashi1,
  4. Nobuo Fuke2,
  5. Sho Osonoi1,
  6. Yuki Takeuchi1,
  7. Kanichiro Wada3,
  8. Akiko Igawa4,
  9. Saori Ogasawara1,
  10. Yasuyuki Ishibashi3,
  11. Kenichi Hakamada4,
  12. Soroku Yagihashi1,
  13. Shigeyuki Nakaji5
  1. 1Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  2. 2Innovation Division, KAGOME Co, Ltd, Tochigi, Japan
  3. 3Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  4. 4Department of Gastrointestinal Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  5. 5Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  1. Correspondence to Dr Hiroki Mizukami; hirokim{at}hirosaki-u.ac.jp

Abstract

Introduction Small fiber neuropathy (SFN) is an early manifestation in diabetic polyneuropathy (DPN); however, the mechanisms are not fully understood. In diabetes, SFN is presumed to be common in individuals with overt DPN, enhancing activation of polyol pathway, oxidative stress, advanced glycation end products (AGEs), and inflammation. We explored the relationship between clinicohematological factors related to DPN and pain sensation in the Japanese population.

Research design and methods We conducted a population-based study, recruiting 1030 individuals (average age 54.4±0.5 years), in 2017, to participate in our Iwaki project. After initial screening by fasting blood glucose and glycohemoglobin A1c (HbA1c) measurements, the subjects were categorized into control (n=894), type 2 diabetes (n=81), and impaired fasting glucose (n=55) groups. Clinical data were gathered, and relationships between pain threshold from intraepidermal electrical stimulation (PINT) and DPN were examined by analysis of variance, post hoc test, and χ2 tests to study correlations among and between groups of the clinical data and DPN.

Results Univariate linear regression analyses showed significant correlations between PINT and serum lipopolysaccharide-binding protein (LBP) level (ß=0.1025, p=0.001). Adjustments for the clinical measurements confirmed a positive correlation (ß=0.070, p=0.034). Logistic regression analysis revealed high LBP value (>6.7 mg/dL) as a significant risk factor toward abnormal PINT (≥0.35 mA). LBP significantly correlated with the high-sensitivity C reactive protein, inflammation marker, elevated similarly in both pre-diabetic and overt-diabetic groups, compared with controls, but it did not correlate with a decreased Achilles tendon reflex. In contrast, urine 8-hydroxy-2'-deoxyguanosine, oxidative stress marker, and pentosidine, AGEs, markedly increased in individuals with type 2 diabetes with high HbA1c.

Conclusions Individuals with high LBP exhibited an elevated PINT in the Japanese population. Low level of inflammation evoked by metabolic endotoxemia is possibly implicated in the pathophysiology of SFN from pre-diabetic stage.

  • diabetic neuropathies
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2020-001739

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    Footnotes

    • Contributors KK: conducted the study for the measurement of pain threshold from intraepidermal electrical stimulation (PINT), discussed and interpreted the results, and contributed to drafting the manuscript. HM: designed and conducted the study for the measurement of PINT, discussed and interpreted the results, and contributed to the manuscript draft. CI: conducted the study for the measurement of PINT, and interpreted and discussed the results. NF: conducted the study for the measurement of antioxidant substances, including lipopolysaccharide-binding protein, interpreted and discussed the results. SOs, AI and SOg: conducted the study for the measurement of PINT, and interpreted and discussed the results. KW: conducted the study for the measurement of Achilles tendon reflex, and interpreted and discussed the results. YT, YI, SY and KH: interpreted and discussed the results. SN: designed and conducted the Iwaki study, and interpreted and discussed the results.

    • Funding This work was supported by JST COI Grant Number JPMJCE1302.

    • Disclaimer Electrodes for intraepidermal electrical stimulation were supplied by Nihon Kohden Corp, Tokyo, Japan.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Hirosaki University School of Medicine (number 2017–026).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. Data used during the study are available from the corresponding author by request.