Abstract
BackgroundAlthough bilirubin has been generally regarded as a waste with potential neurotoxicity at high levels, a few clinical studies suggest a potential protective role of physiological serum total bilirubin (TBIL) concentrations in diabetic peripheral neuropathy (DPN). However, the pathological mechanisms underlying the relationship remain poorly understood. The objective of this study was to explore the relationship between serum TBIL and DPN, and clinical and laboratory parameters.MethodsSerum TBIL was measured in 1342 patients with type 2 diabetes mellitus (T2DM). The relationship between TBIL and DPN and other parameters was analyzed.ResultsSerum TBIL levels were significantly lower in T2DM patients with DPN, and were independently and negatively associated with vibration perception thresholds (VPT) (P < 0.01 or P < 0.05). Moreover, serum TBIL was negatively associated with neutrophil and white blood cell counts, fibrinogen, and the prevalence of hypertension, diabetic foot ulceration, peripheral arterial disease, diabetic nephropathy and diabetic retinopathy (P < 0.01 or P < 0.05). Additionally, serum TBIL was an independent decisive factor for the presence of DPN after multivariate adjustment. Compared to the highest quartile of TBIL, the lower quartiles were associated with a significantly increased risk of DPN (P < 0.01). Last but most importantly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for serum TBIL to predict DPN was 10.75 μmol/L (sensitivity 54.6% and specificity 62.9%).ConclusionsThese findings suggest that lower physiological serum TBIL may be associated with the presence of DPN due to its decreased anti-inflammatory and vascular protective effects.
Highlights
Bilirubin has been generally regarded as a waste with potential neurotoxicity at high levels, a few clinical studies suggest a potential protective role of physiological serum total bilirubin (TBIL) concentrations in diabetic peripheral neuropathy (DPN)
Association of serum TBIL with anthropometric, biochemical and clinical parameters in study subjects we analyzed the relationship of serum TBIL with various other parameters by using simple correlations
In all type 2 diabetes mellitus (T2DM) patients, serum TBIL levels were positively associated with diastolic blood pressure (DBP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), ApoA, lowdensity lipoprotein cholesterol (LDL-C), direct bilirubin (DBIL), indirect bilirubin (IBIL), liver enzymes, and estimated glomerular filtration rate (eGFR), and negatively with age, sex, diabetic duration, Pulse pressure (PP), TG, ApoB/ApoA, neutrophil and white blood cell (WBC) counts, fibrinogen, urinary albumin-to-creatinine ratio (ACR), Crea, vibration perception thresholds (VPT) values, and the prevalence of hypertension, diabetic foot ulceration (DFU), peripheral arterial disease (PAD), DPN, diabetic nephropathy (DN) and diabetic retinopathy (DR) (P < 0.01 or P < 0.05; Table 2)
Summary
Bilirubin has been generally regarded as a waste with potential neurotoxicity at high levels, a few clinical studies suggest a potential protective role of physiological serum total bilirubin (TBIL) concentrations in diabetic peripheral neuropathy (DPN). Numerous recent studies have reported that bilirubin acts as a potent cellular antiapoptotic, antioxidant, anti-inflammatory, and immunoregulatory agent at normal to mildly elevated levels, pointing to a cytoprotective and neuroprotective effect of bilirubin [5,6,7] Consistent with this notion, serum bilirubin levels have been reported to be inversely associated with the prevalence and the severity of cardiovascular autonomic neuropathy (CAN) [5] and the presence and progression of DPN including distal symmetrical polyneuropathy (DSPN) [2, 8], and positively associated with hands and feet electrochemical skin conductance levels for reflecting sudomotor function [9], and corneal nerve fibers morphology for reflecting small nerve fibers (unmyelinated C-fibers) dysfunction [10] in patients with T2DM. The potential associations among serum TBIL and liver enzymes, metabolic parameters, inflammatory markers, and other diabetic micro- and macrovascular complications were evaluated
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