Vol. 149 No. 4344 (2019)
Neuregulin-4 is associated with plasma glucose and increased risk of type 2 diabetes mellitus
- Mehmet Z. Kocak
- Gulali Aktas
- Edip Erkus
- Ozgur M. Yis
- Tuba T. Duman
- Burcin M. Atak
- Haluk Savli
Neuregulin-4 is a cytokine with many functions and is primarily produced by fat tissue.
AIM OF THE STUDY
The aim of the study was to observe the relationship between serum neuregulin-4 levels and diabetes regulation in type 2 diabetes mellitus (T2DM), and to compare neuregulin-4 levels of diabetic subjects with those in healthy controls.
Patients with T2DM were included to the study. Healthy subjects were enrolled as controls. Subjects with T2DM with glycated haemoglobin (HbA1c) <7% were classed as well controlled and those with HbA1c ≥7% were classed as poorly controlled. Neuregulin-4 levels of the study and control groups were compared.
The neuregulin-4 levels of the poorly controlled T2DM, well-controlled T2DM and control groups were significantly different (p = 0.005). Neuregulin-4 was significantly correlated with fasting plasma glucose (r = 0.247, p = 0.002) but not with HbA1c. In a regression analysis model, 0.1 point elevation in neuregulin-4 levels increased the rate of existence of T2DM 4.4-fold (odds ratio 4.4, 95% confidence interval 1.26–15.1; p = 0.02).
Neuregulin-4 is significantly increased in patients with T2DM compared with control subjects, which means that it could be a marker of T2DM. Since neuregulin-4 was correlated with fasting glucose, we suggest that elevated neuregulin-4 could predict poor control in T2DM for short periods when HbA1c is not useful. Moreover, one unit elevation in neuregulin-4 (0.1 ng/ml) increases the rate of existence of T2DM 4.4-fold, independently from other variables.
- Fève B, Bastard C, Fellahi S, Bastard J-P, Capeau J. New adipokines. Ann Endocrinol (Paris). 2016;77(1):49–56. doi:.https://doi.org/10.1016/j.ando.2016.01.001
- Jiang J, Lin M, Xu Y, Shao J, Li X, Zhang H, et al. Circulating neuregulin 4 levels are inversely associated with subclinical cardiovascular disease in obese adults. Sci Rep. 2016;6(1):36710. doi:.https://doi.org/10.1038/srep36710
- Pfeifer A. NRG4: an endocrine link between brown adipose tissue and liver. Cell Metab. 2015;21(1):13–4. doi:.https://doi.org/10.1016/j.cmet.2014.12.008
- Ma Y, Gao M, Liu D. Preventing high fat diet-induced obesity and improving insulin sensitivity through neuregulin 4 gene transfer. Sci Rep. 2016;6(1):26242. doi:.https://doi.org/10.1038/srep26242
- Wang G-X, Zhao X-Y, Meng Z-X, Kern M, Dietrich A, Chen Z, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med. 2014;20(12):1436–43. doi:.https://doi.org/10.1038/nm.3713
- Zhang L, Fu Y, Zhou N, Cheng X, Chen C. Circulating neuregulin 4 concentrations in patients with newly diagnosed type 2 diabetes: a cross-sectional study. Endocrine. 2017;57(3):535–8. doi:.https://doi.org/10.1007/s12020-017-1324-3
- Kang YE, Kim JM, Choung S, Joung KH, Lee JH, Kim HJ, et al. Comparison of serum Neuregulin 4 (Nrg4) levels in adults with newly diagnosed type 2 diabetes mellitus and controls without diabetes. Diabetes Res Clin Pract. 2016;117:1–3. doi:.https://doi.org/10.1016/j.diabres.2016.04.007
- Cai C, Lin M, Xu Y, Li X, Yang S, Zhang H. Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study. BMC Med. 2016;14(1):165. doi:.https://doi.org/10.1186/s12916-016-0703-6
- Dai Y-N, Zhu J-Z, Fang Z-Y, Zhao D-J, Wan X-Y, Zhu H-T, et al. A case-control study: Association between serum neuregulin 4 level and non-alcoholic fatty liver disease. Metabolism. 2015;64(12):1667–73. doi:.https://doi.org/10.1016/j.metabol.2015.08.013
- Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787–94. doi:.https://doi.org/10.1172/JCI7231
- Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840–6. doi:.https://doi.org/10.1038/nature05482
- Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362(9):800–11. doi:.https://doi.org/10.1056/NEJMoa0908359
- Khaw K-T, Wareham N, Luben R, Bingham S, Oakes S, Welch A, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322(7277):15–8. doi:.https://doi.org/10.1136/bmj.322.7277.15
- Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI, Arumugam M, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest. 2015;125(1):458. doi:.https://doi.org/10.1172/JCI80223
- Rosell M, Kaforou M, Frontini A, Okolo A, Chan Y-W, Nikolopoulou E, et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab. 2014;306(8):E945–64. doi:.https://doi.org/10.1152/ajpendo.00473.2013
- Chen LL, Peng MM, Zhang JY, Hu X, Min J, Huang QL, et al. Elevated circulating Neuregulin4 level in patients with diabetes. Diabetes Metab Res Rev. 2017;33(4):e2870. doi:.https://doi.org/10.1002/dmrr.2870
- Yan P-J, Xu Y, Wan Q, Feng J, Li H, Gao C-L, et al. Decreased plasma neuregulin 4 concentration is associated with increased high-sensitivity C-reactive protein in newly diagnosed type 2 diabetes mellitus patients: a cross-sectional study. Acta Diabetol. 2017;54(12):1091–9. doi:.https://doi.org/10.1007/s00592-017-1044-4
- Yan P, Xu Y, Wan Q, Feng J, Li H, Yang J, et al. Plasma Neuregulin 4 Levels Are Associated with Metabolic Syndrome in Patients Newly Diagnosed with Type 2 Diabetes Mellitus. Dis Markers. 2018;2018:6974191. doi:.https://doi.org/10.1155/2018/6974191
- South JC, Blackburn E, Brown IR, Gullick WJ. The neuregulin system of ligands and their receptors in rat islets of langerhans. Endocrinology. 2013;154(7):2385–92. doi:.https://doi.org/10.1210/en.2012-2133
- McElroy SJ, Castle SL, Bernard JK, Almohazey D, Hunter CJ, Bell BA, et al. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol. 2014;184(10):2768–78. doi:.https://doi.org/10.1016/j.ajpath.2014.06.015
- Schumacher MA, Hedl M, Abraham C, Bernard JK, Lozano PR, Hsieh JJ, et al. ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis. 2017;8(2):e2622. doi:.https://doi.org/10.1038/cddis.2017.42