Lipopolysaccharide-binding protein is a distinctive biomarker of abnormal pain threshold in the general Japanese population

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.