Letter: GDF15 Is a Novel Biomarker for Impaired Fasting Glucose (Diabetes Metab J 2014;38:472-9)

Article information

Diabetes Metab J. 2015;39(1):82-83
Publication date (electronic) : 2015 February 16
doi : https://doi.org/10.4093/dmj.2015.39.1.82
1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
2Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Corresponding author: Bo Kyung Koo. Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 156-707, Korea. bokyungkoomd@gmail.com

Growth differentiation factor-15 (GDF15) is widely distributed in mammalian tissues and has been shown to play multiple roles in inflammation, cancer, and cardiovascular diseases [1,2]. It has protective roles in tissue injury or inflammation [1,3,4]; acute tissue injury induces GDF15 level increased compensatively [5,6]. In addition, the fact that overexpression of GDF15 results in improved insulin sensitivity [7,8] and resistance to both genetic and dietary-induced obesity [8], whereas genetic deletion of GDF15 increases glucose level in diabetic rat model [9] supports its favorable effect on metabolic diseases.

Despite its beneficial role in experimental studies, subjects with chronic diseases such as cancer, cardiovascular diseases, and metabolic disorders showed paradoxically elevated level of GDF15 [1]. GDF15 level was also increased in subjects with diabetes or prediabetes [10,11]; however, its level in other chronic diseases (e.g., cardiovascular disease) is glucose-independent [12,13]. Cardiovascular disease has been consistently reported to be associated with elevated GDF15 level [6,12,14], and GDF15 is an independent risk factor of cardiovascular disease even after adjusting for glucose level [12,13].

Hong et al. [11] showed that GDF15 levels were elevated in impaired fasting glucose (IFG) and diabetic groups compared with normal glucose tolerance (NGT) group and suggested GDF15 as a novel diagnostic marker for IFG. Considering the increasing epidemiology of IFG or impaired glucose tolerance (IGT) and their impact on cardiovascular disease risk, clinically easier screening tools for the detection of IFG or IGT might be important. However, several things should be considered to address whether GDF15 is a useful diagnostic marker for IFG. First, the main determinant of GDF15 should be investigated. Hong et al. [11] showed the significant correlates of GDF15 levels in monovariate analysis. I wonder what the independent determinants of GDF15 level are in multivariate model including glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profile. Even in the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial which showed high GDF15 level is a risk factor for the progression of glucose intolerance, GDF15 concentration was higher only in individuals with IGT but not in those with IFG compared with those with NGT [10]. IGT state has been reported to show higher peripheral insulin resistance [15] and higher cardiovascular risk as compared with IFG [16]. The results of XENDOS trial [10] and the phenotype of transgenic mouse model [7,8] implied that GDF15 concentration might reflect insulin resistance rather than glucose level itself. HOMA-IR is a very useful marker for insulin resistance; however, it is not a diagnostic marker of IFG or IGT. Second, measurement of hemoglobin A1c (HbA1c) along with glucose level is a better validated tool than measuring GDF15 for the diagnosis of prediabetes. What is the strength of GDF15 in the diagnosis of IFG compared with HbA1c? The area under the receiver operating characteristic curve of GDF15 for detection of IFG was less than 0.7 in Hong's study [11], which implied GDF15 is not a useful diagnostic marker for IFG [17].


No potential conflict of interest relevant to this article was reported.


1. Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-beta family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev 2013;24:373–384. 23787157.
2. Hur KY. Is GDF15 a novel biomarker to predict the development of prediabetes or diabetes? Diabetes Metab J 2014;38:437–438. 25541606.
3. Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, Bolomini-Vittori M, Korf-Klingebiel M, Napp LC, Hansen B, Kanwischer A, Bavendiek U, Beutel G, Hapke M, Sauer MG, Laudanna C, Hogg N, Vestweber D, Wollert KC. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 2011;17:581–588. 21516086.
4. Rossaint J, Vestweber D, Zarbock A. GDF-15 prevents platelet integrin activation and thrombus formation. J Thromb Haemost 2013;11:335–344. 23231375.
5. Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 2005;23:543–548. 15897808.
6. Stiermaier T, Adams V, Just M, Blazek S, Desch S, Schuler G, Thiele H, Eitel I. Growth differentiation factor-15 in Takotsubo cardiomyopathy: diagnostic and prognostic value. Int J Cardiol 2014;173:424–429. 24681016.
7. Wang X, Chrysovergis K, Kosak J, Kissling G, Streicker M, Moser G, Li R, Eling TE. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging (Albany NY) 2014;6:690–704. 25239873.
8. Wang X, Chrysovergis K, Kosak J, Eling TE. Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity. Obesity (Silver Spring) 2014;22:1256–1263. 24124102.
9. Mazagova M, Buikema H, van Buiten A, Duin M, Goris M, Sandovici M, Henning RH, Deelman LE. Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes. Am J Physiol Renal Physiol 2013;305:F1249–F1264. 23986522.
10. Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, Wollert KC. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol 2012;167:671–678. 22918303.
11. Hong JH, Chung HK, Park HY, Joung KH, Lee JH, Jung JG, Kim KS, Kim HJ, Ku BJ, Shong M. GDF15 is a novel biomarker for impaired fasting glucose. Diabetes Metab J 2014;38:472–479. 25541611.
12. Wallentin L, Hijazi Z, Andersson U, Alexander JH, De Caterina R, Hanna M, Horowitz JD, Hylek EM, Lopes RD, Asberg S, Granger CB, Siegbahn A. ARISTOTLE Investigators. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014;130:1847–1858. 25294786.
13. Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P. Usefulness of growth differentiation factor-15 levels to predict diabetic cardiomyopathy in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2014;114:890–894. 25073564.
14. Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB, Davies JE, Ng LL. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009;30:1057–1065. 19168526.
15. Meyer C, Pimenta W, Woerle HJ, Van Haeften T, Szoke E, Mitrakou A, Gerich J. Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans. Diabetes Care 2006;29:1909–1914. 16873801.
16. DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol 2011;108(3 Suppl):3B–24B.
17. Zhu W, Zeng N, Wang N. Sensitivity, Specificity, Accuracy, Associated Confidence Interval and ROC Analysis with Practical SAS Implementations In : Proceedings of The SAS Conference: NESUG proceedings: Health Care and Life Sciences; 2010 Nov 14-17; Baltimore, MD: Lex Jansen; 2010. p. 9.

Article information Continued