Changes of circulating neuregulin 4 and its relationship with 25-hydroxy vitamin D and other diabetic vascular complications in patients with diabetic peripheral neuropathy

Abstract

Background: Neuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), however, the pathological mechanism remains poorly understood. The purpose of our study was to investigate the association of circulating Nrg4 with DPN and 25-hydroxy vitamin D [25(OH)D], a multifunctional secosteroid hormone that regulates other neurotrophic factors and adipokines gene expression, and other diabetic vascular complications. Methods: Circulating Nrg4 levels were measured with an ELISA kit in 164 newly diagnosed type 2 diabetes mellitus (nT2DM) patients. The relationship between circulating Nrg4 and DPN and other parameters was analyzed. Results: Circulating Nrg4 levels were significantly lower in nT2DM patients with DPN than those without, and subjects in the highest quartile of circulating Nrg4 had significantly lower vibration perception threshold (VPT), the prevalence of DPN, the proportion of persons with VPT > 25 V, and significantly higher circulating 25(OH)D (all P < 0.01). Moreover, circulating Nrg4 was positively and independently associated with 25(OH)D, and was negatively with VPT (P < 0.01 or P < 0.05), but showed no associations with the prevalence of peripheral arterial disease, diabetic nephropathy, and diabetic retinopathy (all P > 0.05). Additionally,the prevalence of DPN and risk of DPN development were progressively decreased with increasing circulating Nrg4 quartiles, independently of potential confounding factors. Conclusions: These data demonstrate that decreased levels of circulating Nrg4 might lead to the development of DPN through its close interaction with circulating 25(OH)D not with other diabetic vascular complications. Further prospective studies are needed to identify our findings in these populations.

Diagnostic Value of the Combined Measurement of Serum HCY and NRG4 in Type 2 Diabetes Mellitus with Early Complicating Diabetic Nephropathy

“…Some studies have found that the level of circulating NRG4 in patients with metabolic syndrome is lower than that in the healthy control group, and the concentration of NRG4 is negatively correlated with the risk of developing metabolic syndrome, and NRG4 concentration may be a protective factor [ 33 ]. However, studies have found no correlation between the circulating NRG4 level and the prevalence of diabetic nephropathy and diabetic retinopathy [ 34 ]. In our study, through the analysis of large sample data, it was found that NRG4 was closely related to the incidence of HCY and DN, and the combination of NRG and HCY had excellent predictive efficacy in predicting early DN of T2DM.…”

Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice

“…Neuregulin-4 is primarily secreted by brown adipose tissue. Clinical studies revealed that a low serum level of neuregulin-4 was associated with diabetes [ 298 , 299 ]. Emerging evidence has shown that neuregulin-4 improved systolic dysfunction, ameliorated cardiac fibrosis, and prevented cardiomyocyte death in diabetic mice [ 257 ].…”

Neuregulin 4 as a novel adipokine in energy metabolism

“…A cross-sectional study including 132 Chinese patients with T2DM demonstrated that serum Nrg4 levels were reduced in diabetic peripheral neuropathy (DPN) and significantly associated with its development, further implicating the anti-inflammatory and metabolic benefits of Nrg4 in T2DM ( Yan et al, 2019 ). Another study ( Yan et al, 2020 ) suggested that serum Nrg4 in DPN patients was independently and positively correlated with 25-hydroxy vitamin D, a hormone that modulates neurotrophic factors and exerts neuronal trophic effects, which seemed to indicate that Nrg4 exerted beneficial effects by interacting with this vitamin. Another study found that serum Nrg4 levels could be a promising predictive biomarker of diabetic microvascular complications with a sensitivity of 82.1% ( Kocak et al, 2020 ).…”