Relationship Between Circulating Netrin-1 Concentration, Impaired Fasting Glucose, and Newly Diagnosed Type 2 Diabetes

Jisook Yim, Gyuri Kim, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Jeong-Ho Kim, Jin Won Cho, Sang-Guk Lee, Yong-Ho Lee, Jisook Yim, Gyuri Kim, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Jeong-Ho Kim, Jin Won Cho, Sang-Guk Lee, Yong-Ho Lee

Abstract

Background: The protein netrin-1 has demonstrated anti-inflammatory, tissue regeneration, and immune modulation properties. Although inflammation is a major contributing factor in the development of insulin resistance and type 2 diabetes, little is known about a possible relationship between serum netrin-1 and type 2 diabetes. Therefore, we investigated the association between circulating levels of netrin-1 and glycometabolic parameters predictive of type 2 diabetes. Methods: Serum samples were collected from 41 normal controls, 85 subjects with impaired fasting glucose (IFG), and 92 subjects with newly diagnosed type 2 diabetes. Clinical and laboratory parameters were assessed and netrin-1 levels were measured by commercial enzyme-linked immunosorbent assay. Spearman correlation analyses and multivariable-adjusted regression analyses were conducted to examine the relationship between serum netrin-1 levels and glycometabolic parameters. Results: Serum netrin-1 levels in subjects with type 2 diabetes or IFG were significantly higher compared to normal controls (441.0, 436.6, and 275.9 pg/mL, respectively; P for trend < 0.001). Serum netrin-1 levels were significantly positively correlated with fasting glucose, HbA1c, and insulin resistance index (all Ps < 0.01). Serum netrin-1 levels were independently associated with IFG or type 2 diabetes (standardized β = 0.405, P < 0.001) after adjusting for covariates and potential confounders. In addition, the receiver operating characteristic (ROC) analysis showed that serum netrin-1 levels could identify the presence of IFG and type 2 diabetes with the area under the ROC curve (AUC) of 0.784 (P < 0.001). Conclusions: Our results suggest that elevated serum netrin-1 levels are significantly associated with the presence of IFG and type 2 diabetes.

Keywords: Netrin-1; impaired fasting glucose; inflammation; relationship; type 2 diabetes.

Figures

Figure 1
Figure 1
Comparison of serum netrin concentrations according to glycemic status. Each horizontal line indicates the mean with 95% confidence interval. IFG, impaired fasting glucose.
Figure 2
Figure 2
A ROC curve with serum netrin concentrations for the prediction of IFG or type 2 diabetes. IFG, impaired fasting glucose; ROC, receiver operating characteristic.

References

    1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature (2001) 414:782–7. 10.1038/414782a
    1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diab Care (2004) 27:1047–53. 10.2337/diacare.27.5.1047
    1. Brown JB, Pedula KL, Bakst AW. The progressive cost of complications in type 2 diabetes mellitus. Arch Intern Med. (1999) 159:1873–80.
    1. Shi Z, Zhen S, Zimmet PZ, Zhou Y, Zhou Y, Magliano DJ, et al. . Association of impaired fasting glucose, diabetes and dietary patterns with mortality: a 10-year follow-up cohort in Eastern China. Acta Diabetol (2016) 53:799–806. 10.1007/s00592-016-0875-8
    1. Kim NH, Kwon TY, Yu S, Kim NH, Choi KM, Baik SH, et al. . Increased vascular disease mortality risk in prediabetic korean adults is mainly attributable to ischemic stroke. Stroke (2017) 48:840–5. 10.1161/strokeaha.116.015947
    1. Lee YH, Armstrong EJ, Kim G, Oh J, Kang SM, Lee BW, et al. . Undiagnosed diabetes is prevalent in younger adults and associated with a higher risk cardiometabolic profile compared to diagnosed diabetes. Am Heart J. (2015) 170:760–9 e2. 10.1016/j.ahj.2015.07.024
    1. Noh J. The Diabetes epidemic in Korea. Endocrinol Metab. (2016) 31:349–53. 10.3803/EnM.2016.31.3.349
    1. Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell (1994) 78:409–24.
    1. Colamarino SA, Tessier-Lavigne M. The axonal chemoattractant netrin-1 is also a chemorepellent for trochlear motor axons. Cell (1995) 81:621–9.
    1. Mirakaj V, Gatidou D, Potzsch C, Konig K, Rosenberger P. Netrin-1 signaling dampens inflammatory peritonitis. J Immunol. (2011) 186:549–55. 10.4049/jimmunol.1002671
    1. Srinivasan K, Strickland P, Valdes A, Shin GC, Hinck L. Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis. Dev Cell (2003) 4:371–82. 10.1016/S1534-5807(03)00054-6
    1. Wilson BD, Ii M, Park KW, Suli A, Sorensen LK, Larrieu-Lahargue F, et al. . Netrins promote developmental and therapeutic angiogenesis. Science (2006) 313:640–4. 10.1126/science.1124704
    1. Arakawa H. Netrin-1 and its receptors in tumorigenesis. Nat Rev Cancer (2004) 4:978–87. 10.1038/nrc1504
    1. Rosenberger P, Schwab JM, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia JC, et al. . Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol. (2009) 10:195–202. 10.1038/ni.1683
    1. He J, Zhao Y, Deng W, Wang DX. Netrin-1 promotes epithelial sodium channel-mediated alveolar fluid clearance via activation of the adenosine 2B receptor in lipopolysaccharide-induced acute lung injury. Respiration (2014) 87:394–407. 10.1159/000358066
    1. Mirakaj V, Thix CA, Laucher S, Mielke C, Morote-Garcia JC, Schmit MA, et al. . Netrin-1 dampens pulmonary inflammation during acute lung injury. Am J Respir Crit Care Med. (2010) 181:815–24. 10.1164/rccm.200905-0717OC
    1. Chen J, Cai QP, Shen PJ, Yan RL, Wang CM, Yang DJ, et al. . Netrin-1 protects against L-Arginine-induced acute pancreatitis in mice. PLoS ONE (2012) 7:e46201. 10.1371/journal.pone.0046201
    1. Mao X, Xing H, Mao A, Jiang H, Cheng L, Liu Y, et al. . Netrin-1 attenuates cardiac ischemia reperfusion injury and generates alternatively activated macrophages. Inflammation (2014) 37:573–80. 10.1007/s10753-013-9771-3
    1. Ke T, Wu Y, Li L, Liu Y, Yao X, Zhang J, et al. . Netrin-1 ameliorates myocardial infarction-induced myocardial injury: mechanisms of action in rats and diabetic mice. Hum Gene Ther. (2014) 25:787–97. 10.1089/hum.2014.021
    1. Layne K, Ferro A, Passacquale G. Netrin-1 as a novel therapeutic target in cardiovascular disease: to activate or inhibit? Cardiovasc Res. (2015) 107:410–9. 10.1093/cvr/cvv201
    1. Park KW, Crouse D, Lee M, Karnik SK, Sorensen LK, Murphy KJ, et al. . The axonal attractant Netrin-1 is an angiogenic factor. Proc Natl Acad Sci USA. (2004) 101:16210–5. 10.1073/pnas.0405984101
    1. Zhang J, Cai H. Netrin-1 prevents ischemia/reperfusion-induced myocardial infarction via a DCC/ERK1/2/eNOS s1177/NO/DCC feed-forward mechanism. J Mol Cell Cardiol. (2010) 48:1060–70. 10.1016/j.yjmcc.2009.11.020
    1. Bloomgarden ZT. Inflammation and insulin resistance. Diabetes Care (2003) 26:1619–23. 10.2337/diacare.26.5.1619
    1. Kang YM, Kim F, Lee WJ. Role of NO/VASP Signaling pathway against obesity-related inflammation and insulin resistance. Diabetes Metab J. (2017) 41:89–95. 10.4093/dmj.2017.41.2.89
    1. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. (2004) 25:4–7. 10.1016/j.it.2003.10.013
    1. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care (2018) 1(Suppl. 1):S13–27. 10.2337/dc18-S002
    1. World Health Organization Regional Office for the Western Pacific. The Asian-Pacific Perspective: Redefining Obesity and Its treatment. Sydney, NSW: Health Communications Australia Pty Limited; (2000). Available online at:
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia (1985) 28:412–9.
    1. Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care (1998) 21:2191–2.
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, III, Feldman HI, et al. . A new equation to estimate glomerular filtration rate. Ann Intern Med. (2009) 150:604–12. 10.7326/0003-4819-150-9-200905050-00006
    1. Ly NP, Komatsuzaki K, Fraser IP, Tseng AA, Prodhan P, Moore KJ, et al. . Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci USA. (2005) 102:14729–34. 10.1073/pnas.0506233102
    1. Ramesh G, Krawczeski CD, Woo JG, Wang Y, Devarajan P. Urinary netrin-1 is an early predictive biomarker of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol. (2010) 5:395–401. 10.2215/cjn.05140709
    1. Jayakumar C, Nauta FL, Bakker SJ, Bilo H, Gansevoort RT, Johnson MH, et al. . Netrin-1, a urinary proximal tubular injury marker, is elevated early in the time course of human diabetes. J Nephrol. (2014) 27:151–7. 10.1007/s40620-014-0055-2
    1. White JJ, Mohamed R, Jayakumar C, Ramesh G. Tubular injury marker netrin-1 is elevated early in experimental diabetes. J Nephrol. (2013) 26:1055–64. 10.5301/jn.5000303
    1. Tak E, Ridyard D, Badulak A, Giebler A, Shabeka U, Werner T, et al. . Protective role for netrin-1 during diabetic nephropathy. J Mol Med. (2013) 91:1071–80. 10.1007/s00109-013-1041-1
    1. Mohamed R, Jayakumar C, Ranganathan PV, Ganapathy V, Ramesh G. Kidney proximal tubular epithelial-specific overexpression of netrin-1 suppresses inflammation and albuminuria through suppression of COX-2-mediated PGE2 production in streptozotocin-induced diabetic mice. Am J Pathol. (2012) 181:1991–2002. 10.1016/j.ajpath.2012.08.014
    1. Tadagavadi RK, Wang W, Ramesh G. Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. J Immunol. (2010) 185:3750–8. 10.4049/jimmunol.1000435
    1. Schlegel M, Kohler D, Korner A, Granja T, Straub A, Giera M, et al. . The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration. Hepatology (2016) 63:1689–705. 10.1002/hep.28347
    1. Ay E, Marakoglu K, Kizmaz M, Unlu A. Evaluation of Netrin-1 Levels and Albuminuria in Patients With Diabetes. J Clin Lab Anal. (2016) 30:972–7. 10.1002/jcla.21965
    1. Ramkhelawon B, Hennessy EJ, Menager M, Ray TD, Sheedy FJ, Hutchison S, et al. . Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med. (2014) 20:377–84. 10.1038/nm.3467
    1. Liu C, Ke X, Wang Y, Feng X, Li Q, Zhang Y, et al. . The level of netrin-1 is decreased in newly diagnosed type 2 diabetes mellitus patients. BMC Endocr Disord. (2016) 16:33. 10.1186/s12902-016-0112-z
    1. Voortman MM, Pekar T, Bachmayer D, Archelos JJ, Stojakovic T, Scharnagl H, et al. . Serum netrin-1 in relation to gadolinium-enhanced magnetic resonance imaging in early multiple sclerosis. Mult Scler J Exp Transl Clin. (2017) 3:2055217317727294. 10.1177/2055217317727294
    1. Barallobre MJ, Pascual M, Del Rio JA, Soriano E. The Netrin family of guidance factors: emphasis on Netrin-1 signalling. Brain Res Brain Res Rev. (2005) 49:22–47. 10.1016/j.brainresrev.2004.11.003
    1. De Breuck S, Lardon J, Rooman I, Bouwens L. Netrin-1 expression in fetal and regenerating rat pancreas and its effect on the migration of human pancreatic duct and porcine islet precursor cells. Diabetologia (2003) 46:926–33. 10.1007/s00125-003-1125-5
    1. Gao S, Zhang X, Qin Y, Xu S, Zhang J, Wang Z, et al. . Dual actions of Netrin-1 on islet insulin secretion and immune modulation. Clin Sci. (2016) 130:1901–11. 10.1042/cs20160133
    1. Toque HA, Fernandez-Flores A, Mohamed R, Caldwell RB, Ramesh G, Caldwell RW. Netrin-1 is a novel regulator of vascular endothelial function in diabetes. PLoS ONE (2017) 12:e0186734. 10.1371/journal.pone.0186734

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