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Endocrine

, Volume 48, Issue 3, pp 848–855 | Cite as

Basal and postprandial change in serum fibroblast growth factor-21 concentration in type 1 diabetic mellitus and in healthy controls

  • Karin Zibar
  • Kristina Blaslov
  • Tomislav Bulum
  • Jadranka Knežević Ćuća
  • Lea Smirčić-Duvnjak
Original Article

Abstract

Fibroblast growth factor-21 (FGF-21) appears to have an important role in glucose and lipid metabolism. FGF-21 secretion is mainly determined by nutritional status. The aim of this study was to measure basal and postprandial FGF-21 and postprandial change of FGF-21 concentration in type 1 diabetes mellitus (T1DM) patients and in healthy controls, and to investigate the differences between the groups. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20–59), disease duration 22 years (3–45), and nine healthy controls, median age 30 years (27–47). Basal and postprandial FGF-21 concentrations were measured by ELISA. The associations of FGF-21 with glucose, lipids, and insulin were analyzed. Individuals with T1DM showed significantly lower basal FGF-21 concentration (P = 0.046) when compared with healthy controls (median value 28.2 vs 104 pg/mL) and had significantly different postprandial change (∆ 30′−0′) of FGF-21 (P = 0.006) in comparison with healthy controls (median value −1.1 vs −20.5 pg/mL). The glucose and lipid status did not correlate with FGF-21. In healthy controls, postprandial insulin level correlated with basal FGF-21 (ρ = 0.7, P = 0.036). Multiple regression analysis showed that they are independently associated after adjustment for confounding factors (β = 1.824, P = 0.04). We describe the pathological pattern of basal and postprandial change of FGF-21 secretion not associated with glucose, lipid levels, or insulin therapy in patients with T1DM. Since FGF-21 has numerous protective metabolic effects in the experimental model, the lower basal FGF-21 concentration in T1DM patients opens the question about the potential role of recombinant FGF-21 therapy.

Keywords

Fibroblast growth factor-21 Type 1 diabetes mellitus C-peptide negative Healthy controls 

Notes

Acknowledgments

The authors would like to thank the laboratory staff at Merkur University Hospital, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Zagreb, Croatia. The work was supported by the Ministry of Science, Education and Sports of the Republic of Croatia Grant 045-1080230-0516.

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical standard

The study protocol was approved by the Ethics Committee of The University of Zagreb School of Medicine and Merkur University Hospital of Zagreb, Croatia.

References

  1. 1.
    A. Kharitonenkov, T.L. Shiyanova, A. Koester, A.M. Ford, R. Micanovic, E.J. Galbreath, G.E. Sandusky, L.J. Hammond, J.S. Moyers, R.A. Owens, J. Gromada, J.T. Brozinick, E.D. Hawkins, V.J. Wroblewski, D.S. Li, F. Mehrbod, S.R. Jaskunas, A.B. Shanafelt, FGF-21 as a novel metabolic regulator. J. Clin. Investig. 115(6), 1627–1635 (2005)CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    M. Mraz, M. Bartlova, Z. Lacinova, D. Michalsky, M. Kasalicky, D. Haluzikova, M. Matoulek, I. Dostalova, V. Humenanska, M. Haluzik, Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin. Endocrinol. 71(3), 369–375 (2009)CrossRefGoogle Scholar
  3. 3.
    W.W. Chen, L. Li, G.Y. Yang, K. Li, X.Y. Qi, W. Zhu, Y. Tang, H. Liu, G. Boden, Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes. 116(1), 65–68 (2008)CrossRefPubMedGoogle Scholar
  4. 4.
    A.O. Chavez, M. Molina-Carrion, M.A. Abdul-Ghani, F. Folli, R.A. Defronzo, D. Tripathy, Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32(8), 1542–1546 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    W.X. Jian, W.H. Peng, J. Jin, X.R. Chen, W.J. Fang, W.X. Wang, L. Qin, Y. Dong, Q. Su, Association between serum fibroblast growth factor 21 and diabetic nephropathy. Metabolism 61(6), 853–859 (2012)CrossRefPubMedGoogle Scholar
  6. 6.
    S.Y. An, M.S. Lee, S.A. Yi, E.S. Ha, S.J. Han, H.J. Kim, D.J. Kim, K.W. Lee, Serum fibroblast growth factor 21 was elevated in subjects with type 2 diabetes mellitus and was associated with the presence of carotid artery plaques. Diabetes Res. Clin. Pract. 96(2), 196–203 (2012)CrossRefPubMedGoogle Scholar
  7. 7.
    F.L. Mashili, R.L. Austin, A.S. Deshmukh, T. Fritz, K. Caidahl, K. Bergdahl, J.R. Zierath, A.V. Chibalin, D.E. Moller, A. Kharitonenkov, A. Krook, Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. Diabetes Metab. Res. Rev. 27(3), 286–297 (2011)CrossRefPubMedGoogle Scholar
  8. 8.
    T. Reinehr, J. Woelfle, R. Wunsch, C.L. Roth, Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J. Clin. Endocrinol. Metab. 97(6), 2143–2150 (2012)CrossRefPubMedGoogle Scholar
  9. 9.
    C. Hale, M.M. Chen, S. Stanislaus, N. Chinookoswong, T. Hager, M. Wang, M.M. Veniant, J. Xu, Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 153(1), 69–80 (2012)CrossRefPubMedGoogle Scholar
  10. 10.
    Y. Murata, M. Konishi, N. Itoh, FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology. J. Nutr. Metab. 2011, 981315 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    F.M. Fisher, P.C. Chui, P.J. Antonellis, H.A. Bina, A. Kharitonenkov, J.S. Flier, E. Maratos-Flier, Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59(11), 2781–2789 (2010)CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    A. Kharitonenkov, J.D. Dunbar, H.A. Bina, S. Bright, J.S. Moyers, C. Zhang, L. Ding, R. Micanovic, S.F. Mehrbod, M.D. Knierman, J.E. Hale, T. Coskun, A.B. Shanafelt, FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho. J. Cell. Physiol. 215(1), 1–7 (2008)CrossRefPubMedGoogle Scholar
  13. 13.
    P. Hojman, M. Pedersen, A.R. Nielsen, R. Krogh-Madsen, C. Yfanti, T. Akerstrom, S. Nielsen, B.K. Pedersen, Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 58(12), 2797–2801 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    T. Uebanso, Y. Taketani, H. Yamamoto, K. Amo, H. Ominami, H. Arai, Y. Takei, M. Masuda, A. Tanimura, N. Harada, H. Yamanaka-Okumura, E. Takeda, Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? PLoS ONE 6(8), e22976 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    H. Yu, F. Xia, K.S. Lam, Y. Wang, Y. Bao, J. Zhang, Y. Gu, P. Zhou, J. Lu, W. Jia, A. Xu, Circadian rhythm of circulating fibroblast growth factor 21 is related to diurnal changes in fatty acids in humans. Clin. Chem. 57(5), 691–700 (2011)CrossRefPubMedGoogle Scholar
  16. 16.
    Y. Xiao, A. Xu, L.S. Law, C. Chen, H. Li, X. Li, L. Yang, S. Liu, Z. Zhou, K.S. Lam, Distinct changes in serum fibroblast growth factor 21 levels in different subtypes of diabetes. J. Clin. Endocrinol. Metab. 97(1), E54–E58 (2012)CrossRefPubMedGoogle Scholar
  17. 17.
    N. Matikainen, M.-R. Taskinen, S. Stennabb, N. Lundbom, A. Hakkarainen, K. Vaaralahti, T. Raivio, Decrease in circulating fibroblast growth factor 21 after an oral fat load is related to postprandial triglyceride-rich lipoproteins and liver fat. Eur. J. Endocrinol. 166, 487–492 (2012)CrossRefPubMedGoogle Scholar
  18. 18.
    Z. Lin, Q. Gong, C. Wu, L. Yu, X. Pan, S. Lin, X. Li, Dynamic change of serum FGF21 levels in response to glucose challenge in human. J. Clin. Endocrinol. Metab. 97, E1224–E1228 (2012)CrossRefPubMedGoogle Scholar
  19. 19.
    World Health Organization, Department of Noncommunicable Disease Surveillance: Definition, diagnosis and classification of diabetes and its complications. Part 1: diagnosis and classification of diabetes mellitus. World Health Organization, Geneva (1999)Google Scholar
  20. 20.
    M. Yang, J. Dong, H. Liu, L. Li, G. Yang, Effects of short-term continuous subcutaneous insulin infusion on fasting plasma fibroblast growth factor-21 levels in patients with newly diagnosed type 2 diabetes mellitus. PLoS One 6, e26359 (2011)CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    S. Kralisch, A. Tonjes, K. Krause, J. Richter, U. Lossner, P. Kovacs, T. Ebert, M. Bluher, M. Stumvoll, M. Fasshauer, Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J. Endocrinol. 216(2), 135–143 (2013)CrossRefPubMedGoogle Scholar
  22. 22.
    R.D. Semba, K. Sun, J.M. Egan, C. Crasto, O.D. Carlson, L. Ferrucci, Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance: the Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 97(4), 1375–1382 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    C. Galman, T. Lundasen, A. Kharitonenkov, H.A. Bina, M. Eriksson, I. Hafstrom, M. Dahlin, P. Amark, B. Angelin, M. Rudling, The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 8(2), 169–174 (2008)CrossRefPubMedGoogle Scholar
  24. 24.
    Y. Shen, X. Ma, J. Zhou, X. Pan, Y. Hao, M. Zhou, Z. Lu, M. Gao, Y. Bao, W. Jia, Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc. Diabetol. 12, 124 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    P. Lee, J. Linderman, S. Smith, R.J. Brychta, R. Perron, C. Idelson, C.D. Werner, K.Y. Chen, F.S. Celi, Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? Osteoporos. Int. 24(12), 3053–3057 (2013)CrossRefPubMedGoogle Scholar
  26. 26.
    L.K. Heilbronn, L.V. Campbell, A. Xu, D. Samocha-Bonet, Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans. PLoS ONE 8(10), e78864 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    A. Bisgaard, K. Sørensen, T.H. Johannsen, J.W. Helge, A.-M. Andersson, A. Juul, Significant gender difference in serum levels of fibroblast growth factor 21 in Danish children and adolescents. Int. J. Pediatr. Endocrinol. 2014, 7 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    T. Coskun, H.A. Bina, M.A. Schneider, J.D. Dunbar, C.C. Hu, Y. Chen, D.E. Moller, A. Kharitonenkov, Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149(12), 6018–6027 (2008)CrossRefPubMedGoogle Scholar
  29. 29.
    J. Xu, D.J. Lloyd, C. Hale, S. Stanislaus, M. Chen, G. Sivits, S. Vonderfecht, R. Hecht, Y.S. Li, R.A. Lindberg, J.L. Chen, D.Y. Jung, Z. Zhang, H.J. Ko, J.K. Kim, M.M. Veniant, Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58(1), 250–259 (2009)CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Karin Zibar
    • 1
  • Kristina Blaslov
    • 1
  • Tomislav Bulum
    • 1
  • Jadranka Knežević Ćuća
    • 2
  • Lea Smirčić-Duvnjak
    • 1
    • 3
  1. 1.Department of Endocrinology and Metabolic Diseases, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic DiseasesMerkur University HospitalZagrebCroatia
  2. 2.Department of Clinical Chemistry and Laboratory MedicineMerkur University HospitalZagrebCroatia
  3. 3.Medical School University of ZagrebZagrebCroatia

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