Journal of Endocrinological Investigation

, Volume 42, Issue 1, pp 53–60 | Cite as

Acromegaly is associated with high fibroblast growth factor-21 levels

  • B. S. YurekliEmail author
  • N. O. Kutbay
  • M. Aksit
  • A. Suner
  • I. Y. Simsir
  • S. Seckiner
  • G. U. Kocabas
  • G. Bozkaya
  • F. Saygili
Original Article



Fibroblast growth factor-21 (FGF-21) is a member of fibroblast growth factor family. Both growth hormone (GH) and FGF-21 take place in the regulation of glucose and lipid metabolism. We aimed to investigate FGF-21 levels in acromegaly which is characterized by excess GH levels and is associated with comorbidities and altered body composition.


We studied 43 subjects (21 females and 22 males, mean age of 50.0 ± 12.8) with acromegaly. The control group consisted of 40 gender- and age-matched subjects (25 females and 15 males, mean age of 48.8 ± 8.8). Acromegaly patients were classified into two groups; active acromegaly (AA; n = 26) and controlled acromegaly (CA; n = 17). Metabolic, anthropometric and laboratory values of subjects were recorded. FGF-21 level was measured by ELISA assay.


Median FGF-21 levels were significantly higher in acromegaly group compared to control group (85.5 vs. 59.0 pg/mL, p = 0.02, respectively). In the multiple regression model, FPG, A1c, HOMA-IR, glucose intolerance, BMI, visceral fat, hs-CRP, presence of hypertension, dyslipidemia and acromegaly were included as independent variables to explain variability of plasma FGF-21 levels in whole study group. The presence of acromegaly was the only determinant of increased FGF-21 levels in the whole study group (β coefficient = 0.253, p = 0.006).


FGF-21 levels were increased significantly in acromegaly group. Increased FGF-21 levels were significantly and independently associated with the state of acromegaly. Acromegaly may also be a FGF-21 resistance state independent from insulin resistance, glucose intolerance, obesity, hypertension and dyslipidemia.


GH FGF-21 Acromegaly 



This research did not receive any specific grant.

Compliance with ethical standards

Conflict of interest

The authors have nothing to disclose.

Ethical approval

The study was approved by Ege University Local Ethic Committee. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all participants.


  1. 1.
    Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK (2011) American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the diagnosis and treatment of acromegaly–2011 update: executive summary. Endocr Pract 17(4):636–646CrossRefGoogle Scholar
  2. 2.
    Katznelson L, Laws ER, Melmed SJ, Molitch ME, Murad MH, Utz A, Wass JA (2014) Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 99(11):3933–3951CrossRefGoogle Scholar
  3. 3.
    Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8(3):235–253. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ (2007) The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148(2):774–781 (Epub 2006 Oct 26) CrossRefGoogle Scholar
  5. 5.
    Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A (2008) Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57(5):1246–1253CrossRefGoogle Scholar
  6. 6.
    Kim WJ, Kim SS, Lee HC, Song SH, Bae MJ, Yi YS, Jeon YK, Kim BH, Kim YK, Kim IJ (2015) Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes. J Korean Med Ssci 30(5):586–590CrossRefGoogle Scholar
  7. 7.
    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281(23):15694–15700. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M (2007) Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282(37):26687–26695CrossRefGoogle Scholar
  9. 9.
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARa and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5(6):426–437. CrossRefPubMedGoogle Scholar
  10. 10.
    Wang H, Qiang L, Farmer SR (2008) Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 28(1):188–200. CrossRefPubMedGoogle Scholar
  11. 11.
    Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ (2000) Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 342(16):1171–1177CrossRefGoogle Scholar
  12. 12.
    Shen Y, Ma X, Zhou J, Pan X, Hao Y, Zhou M, Lu Z, Gao M, Bao Y, Jia W (2013) Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 12:124. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    American Diabetes Association (2015) Diagnosis and classification of diabetes mellitus. Diabetes Care 38:S8–S16CrossRefGoogle Scholar
  14. 14.
    Akyildiz ZI, Polat S, Yurekli BS, Kocabas GU, Tuluce K, Tuluce SY, Kocabas U, Bozkaya G, Yuksel A, Nazli C (2015) Epicardial fat, body mass index, and triglyceride are independent contributors of serum fibroblast growth factor 21 level in obese premenopausal women. J Endocrinol Invest 38(3):361–366. (Epub 2014 Oct 14) CrossRefPubMedGoogle Scholar
  15. 15.
    Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, Lam KS, Xu A (2011) Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 286(40):34559–34566. (Epub 2011 Aug 17) CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop LC (2003) Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults. Eur J Endocrinol 149(6):511–519CrossRefGoogle Scholar
  17. 17.
    Mai K, Andres J, Biedasek K, Weicht J, Bobbert T, Sabath M, Meinus S, Reinecke F, Möhlig M, Weickert MO, Clemenz M, Pfeiffer AF, Kintscher U, Spuler S, Spranger J (2009) Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes 58(7):1532–1538. (Epub 2009 Apr 28) CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mai K, Bobbert T, Groth C, Assmann A, Meinus S, Kraatz J, Andres J, Arafat AM, Pfeiffer AF, Möhlig M, Spranger J (2010) Physiological modulation of circulating FGF21: relevance of free fatty acids and insulin. Am J Physiol Endocrinol Metab 299(1):E126–E130. (Epub 2010 Apr 27) CrossRefPubMedGoogle Scholar
  19. 19.
    Brooks NE, Hjortebjerg R, Henry BE, List EO, Kopchick JJ, Berryman DE (2016) Fibroblast growth factor 21, fibroblast growth factor receptor 1, and β-Klotho expression in bovine growth hormone transgenic and growth hormone receptor knockout mice. Growth Horm IGF Res 30–31:22–30. (Epub 2016 Aug 24) CrossRefPubMedGoogle Scholar
  20. 20.
    Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchick JJ (2004) Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 14(4):309–318CrossRefGoogle Scholar
  21. 21.
    Lin Z, Zhou Z, Liu Y, Gong Q, Yan X, Xiao J, Wang X, Lin S, Feng W, Li X (2011) Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS One 6(4):e18398 (6) CrossRefGoogle Scholar
  22. 22.
    Lundberg J, Höybye C, Krusenstjerna-Hafstrøm T, Bina HA, Kharitonenkov A, Angelin B, Rudling M (2013) Influence of growth hormone on circulating fibroblast growth factor 21 levels in humans. J Intern Med 274(3):227–232. (Epub 2013 Jul 24) CrossRefPubMedGoogle Scholar
  23. 23.
    Halupczok-Żyła J, Jawiarczyk-Przybyłowska A, Skrzypski M, Bolanowski M, Strowski MZ (2017) Fibroblast growth factor 21 in patients with acromegaly. Exp Clin Endocrinol Diabetes 125(10):649–654. (Epub 2017 Sep 20) CrossRefPubMedGoogle Scholar
  24. 24.
    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA (2008) Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 8(1):77–83CrossRefGoogle Scholar
  25. 25.
    Fazeli PK, Misra M, Goldstein M, Miller KK, Klibanski (2010) Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. J Clin Endocrinol Metab 95(1):369–374. (Epub 2009 Nov 19) CrossRefPubMedGoogle Scholar
  26. 26.
    Berryman DE, List EO, Sackmann-Sala L, Lubbers E, Munn R, Kopchick JJ (2011) Growth hormone and adipose tissue: beyond the adipocyte. Growth Hormon IGF Res 21(3):113–123CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2018

Authors and Affiliations

  • B. S. Yurekli
    • 1
    Email author
  • N. O. Kutbay
    • 1
  • M. Aksit
    • 2
  • A. Suner
    • 3
  • I. Y. Simsir
    • 1
  • S. Seckiner
    • 4
  • G. U. Kocabas
    • 5
  • G. Bozkaya
    • 2
  • F. Saygili
    • 1
  1. 1.Division of EndocrinologyEge University Faculty of MedicineIzmirTurkey
  2. 2.Department of BiochemistryIzmir Bozyaka Education and Research HospitalIzmirTurkey
  3. 3.Department of BiostatisticsEge University Faculty of MedicineIzmirTurkey
  4. 4.Department of Nutrition and DieteticsEge University Faculty of MedicineIzmirTurkey
  5. 5.Division of EndocrinologyIzmir Bozyaka Education and Research HospitalIzmirTurkey

Personalised recommendations