Abstract
BackgroundNeuregulin 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.MethodsCirculating 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.ResultsCirculating 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.ConclusionsThese 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.
Highlights
Neuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), the pathological mechanism remains poorly understood
Numerous studies showed that decreased Nrg4 levels were closely associated with obesity, insulin resistance, diabetes mellitus, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, inflammation, oxidative stress, and macrovascular disease such as coronary artery disease, myocardial infarcts, subclinical cardiovascular disease (CVD) in rodents and humans [3, 5,6,7,8,9,10,11,12,13,14,15], while all above factors have been reported to contribute to the development of DNP [1,2,3, 16, 17], suggesting indirectly that Nrg4 appears to play a crucial role in the development of DNP
Circulating levels of Nrg4 and 25(OH)D, vibration perception threshold (VPT) values, age, prevalence of DPN, the proportion of individuals with VPT > 25 V and three or more abnormal DPN screening were significantly different across quartiles of plasma Nrg4 (P < 0.01 or P < 0.05)
Summary
Neuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), the pathological mechanism remains poorly understood. The purpose of our study was to investigate the association of circulating Nrg 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. There is preliminary in vivo evidence that circulating Nrg levels were significantly decreased in newly diagnosed type 2 diabetes mellitus (nT2DM) patients with DPN [3], the pathological mechanism underlying the relationship between decreased plasma Nrg levels and increased risk of DPN remains poorly understood
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