BackgroundNeuregulin4 (Nrg4) is a novel adipokine expressed in adipose tissues, enriched in brown adipose tissue, and able to improve whole-body metabolism in rodent, thus having the potential to treat obesity-associated disorders such as diabetes. However, the association between serum Nrg4 levels and diabetes risk in human remains unclear. This study was designed to examine circulating Nrg4 levels in subjects with different glucose tolerance status. MethodsAge-, sex-, and body mass index-matched subjects (n=310: 83 normal glucose tolerance [NGT], 129 prediabetes, and 96 diabetes) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (Reaction study) were included. Serum Nrg4 was measured via enzyme-linked immunosorbent assay. Basic anthropometric parameters, fasting plasma glucose and 2-hours postload plasma glucose, hemoglobin A(1c), and serum lipid profile were also measured. ResultsThe serum Nrg4 levels were higher in patients with diabetes than those with NGT and prediabetes (diabetes: 396.8[65.9, 709.4], NGT: 80.1[0, 554.1], prediabetes: 168.0[32.9, 463.9] pg/mL [median (interquartile range), both P<0.05]). The Nrg4 concentration was correlated with fasting plasma glucose. When the top versus bottom quartiles of serum Nrg4 concentrations were compared with adjustment for age and sex, an odds ratio of 3.005 was observed in diabetes prevalence, which persisted after adjusting other potential confounding variables. Other nonglucose parameters as body mass index; waist, hip, and neck circumferences; alanine aminotransferase; triglyceride; high-density lipoprotein; uric acid; and estimated glomerular filtration rate were also correlated with serum Nrg4 (P<0.05). ConclusionsThe circulating Nrg4 level is elevated in the prediabetic and diabetic patients compared to control and is an independent risk factor associated with diabetes.