Abstract
Purpose
Fibroblast growth factor (FGF) 21 is a circulating hormone with an important role in metabolic regulation. FGF21 production in humans responds positively to glucose consumption and we hypothesize that serum FGF21 concentration is associated to glycemic control.
Methods
We enrolled 31 patients with type 1 diabetes (T1D) based on their HbA1c (well-regulated (HbA1c <53 mmol/mol), (n = 18) or poorly-regulated (HbA1c >69 mmol/mol), (n = 13). Twelve patients (39%) were diagnosed with retinopathy. Twenty healthy individuals comparable for age and gender distribution were included as a reference group. Serum FGF21, intact FGF21, fibroblast activation protein (FAP), adiponectin, and C-Reactive Protein (CRP) were measured by immunoassays.
Results
No correlation between FGF21 concentration and HbA1c was found. Patients with T1D had lower levels of circulating FGF21 as compared with the reference group, but the difference was nonsignificant (p = 0.12). Dividing the patients according to retinopathy, we found that T1D patients with retinopathy had significantly lower FGF21 concentrations (10.0 ng/L) as compared with the healthy reference group (37.1 ng/L), (p = 0.02). We found significantly higher levels of the FGF21 cleaving enzyme, FAP, in patients with T1D (97.2 μg/L) as compared with the healthy control group (78.5 μg/L), (p = 0.006). Interestingly, serum FAP levels correlated significantly with circulating FGF21 levels in T1D patients, but this correlation was not found in the healthy controls.
Conclusions
We found no association between circulating FGF21 levels and HbA1c. T1D patients with retinopathy had significantly lower FGF21 levels as compared with healthy individuals, but it remains unclear if the lower levels of FGF21 are pathogenically related to the development of microvascular complications. Of note, serum FAP levels were significantly higher in all T1D patients as compared with the healthy individuals.
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References
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). https://doi.org/10.1172/jci23606
J.H. Kim, K.H. Bae, Y.K. Choi, Y. Go, M. Choe, Y.H. Jeon, H.W. Lee, S.H. Koo, J.W. Perfield 2nd, R.A. Harris, I.K. Lee, K.G. Park, Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function. Diabetes Obes. Metab. 17(2), 161–169 (2015). https://doi.org/10.1111/dom.12408
B. Andersen, B.A. Omar, G. Rakipovski, K. Raun, B. Ahren, Fibroblast growth factor 21 prevents glycemic deterioration in insulin deficient mouse models of diabetes. Eur. J. Pharmacol. 764, 189–194 (2015). https://doi.org/10.1016/j.ejphar.2015.07.003
X. Ye, J. Qi, D. Yu, Y. Wu, S. Zhu, S. Li, Q. Wu, G. Ren, D. Li, Pharmacological efficacy of FGF21 analogue, liraglutide, and insulin glargine in treatment of type 2 diabetes. J. Diabetes Complicat. 31(4), 726–734 (2017). https://doi.org/10.1016/j.jdiacomp.2017.01.008
D.R. Dunshee, T.W. Bainbridge, N.M. Kljavin, J. Zavala-Solorio, A.C. Schroeder, R. Chan, R. Corpuz, M. Wong, W. Zhou, G. Deshmukh, J. Ly, D.P. Sutherlin, J.A. Ernst, J. Sonoda, Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. J. Biol. Chem. 291(11), 5986–5996 (2016). https://doi.org/10.1074/jbc.M115.710582
R. Micanovic, D.W. Raches, J.D. Dunbar, D.A. Driver, H.A. Bina, C.D. Dickinson, A. Kharitonenkov, Different roles of N- and C- termini in the functional activity of FGF21. J. Cell. Physiol. 219(2), 227–234 (2009). https://doi.org/10.1002/jcp.21675
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). https://doi.org/10.1210/jc.2011-1930
K. Zibar, K. Blaslov, T. Bulum, J.K. Cuca, L. Smircic-Duvnjak, Basal and postprandial change in serum fibroblast growth factor-21 concentration in type 1 diabetic mellitus and in healthy controls. Endocrine 48(3), 848–855 (2015). https://doi.org/10.1007/s12020-014-0413-9
A. Beenken, M. Mohammadi, The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 8(3), 235–253 (2009). https://doi.org/10.1038/nrd2792
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). https://doi.org/10.1371/journal.pone.0022976
J.R. Dushay, E. Toschi, E.K. Mitten, F.M. Fisher, M.A. Herman, E. Maratos-Flier, Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol. Metab. 4(1), 51–57 (2015). https://doi.org/10.1016/j.molmet.2014.09.008
A.M. Lundsgaard, A.M. Fritzen, K.A. Sjoberg, L.S. Myrmel, L. Madsen, J.F.P. Wojtaszewski, E.A. Richter, B. Kiens, Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol. Metab. 6(1), 22–29 (2017). https://doi.org/10.1016/j.molmet.2016.11.001
E.S. Lauritzen, N. Rittig, E. Bach, N. Moller, M. Bjerre, LPS infusion suppresses serum FGF21 levels in healthy adult volunteers. Endocr. Connect. 6(1), 39–43 (2017). https://doi.org/10.1530/ec-16-0103
J. Frystyk, L. Tarnow, T.K. Hansen, H.H. Parving, A. Flyvbjerg, Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia 48(9), 1911–1918 (2005). https://doi.org/10.1007/s00125-005-1850-z
W. Wente, A.M. Efanov, M. Brenner, A. Kharitonenkov, A. Koster, G.E. Sandusky, S. Sewing, I. Treinies, H. Zitzer, J. Gromada, Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55(9), 2470–2478 (2006). https://doi.org/10.2337/db05-1435
C.L. Johnson, J.Y. Weston, S.A. Chadi, E.N. Fazio, M.W. Huff, A. Kharitonenkov, A. Koester, C.L. Pin, Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 137(5), 1795–1804 (2009). https://doi.org/10.1053/j.gastro.2009.07.064
Z. Fu, Z. Wang, C.H. Liu, Y. Gong, B. Cakir, R. Liegl, Y. Sun, S.S. Meng, S.B. Burnim, I. Arellano, E. Moran, R. Duran, A. Poblete, S.S. Cho, S. Talukdar, J.D. Akula, A. Hellstrom, L.E.H. Smith, Fibroblast growth factor 21 protects photoreceptor function in Type 1 diabetic mice. Diabetes 67(5), 974–985 (2018). https://doi.org/10.2337/db17-0830
B. Emanuelli, S.G. Vienberg, G. Smyth, C. Cheng, K.I. Stanford, M. Arumugam, M.D. Michael, A.C. Adams, A. Kharitonenkov, C.R. Kahn, Interplay between FGF21 and insulin action in the liver regulates metabolism. J. Clin. Investig. 124(2), 515–527 (2014). https://doi.org/10.1172/jci67353
R.J. Samms, J.E. Lewis, L. Norton, F.B. Stephens, C.J. Gaffney, T. Butterfield, D.P. Smith, C.C. Cheng, J.W. Perfield 2nd, A.C. Adams, F.J.P. Ebling, K. Tsintzas, FGF21 is an insulin-dependent postprandial hormone in adult humans. J. Clin. Endocrinol. Metab. 102(10), 3806–3813 (2017). https://doi.org/10.1210/jc.2017-01257
R.P. Hoffman, A.S. Dye, H. Huang, J.A. Bauer, Glycemic variability predicts inflammation in adolescents with type 1 diabetes. J. Pediatr. Endocrinol. Metab. 29(10), 1129–1133 (2016). https://doi.org/10.1515/jpem-2016-0139
X. Li, X. Fan, F. Ren, Y. Zhang, C. Shen, G. Ren, J. Sun, N. Zhang, W. Wang, G. Ning, J. Yang, Serum FGF21 levels are increased in newly diagnosed type 2 diabetes with nonalcoholic fatty liver disease and associated with hsCRP levels independently. Diabetes Res. Clin. Pract. 93(1), 10–16 (2011). https://doi.org/10.1016/j.diabres.2011.02.034
A.L. Coppage, K.R. Heard, M.T. DiMare, Y. Liu, W. Wu, J.H. Lai, W.W. Bachovchin, Human FGF-21 is a substrate of fibroblast activation protein. PLoS ONE 11(3), e0151269 (2016). https://doi.org/10.1371/journal.pone.0151269
L. Duvnjak, M.N. Perkovic, K. Blaslov, Dipeptidyl peptidase-4 activity is associated with urine albumin excretion in type 1 diabetes. J. Diabetes Complicat. 31(1), 218–222 (2017). https://doi.org/10.1016/j.jdiacomp.2016.08.022
C.H. Jung, S.H. Jung, B.Y. Kim, C.H. Kim, S.K. Kang, J.O. Mok, The U-shaped relationship between fibroblast growth factor 21 and microvascular complication in type 2 diabetes mellitus. J. Diabetes Complicat. 31(1), 134–140 (2017). https://doi.org/10.1016/j.jdiacomp.2016.10.017
Q. Li, Y. Zhang, D. Ding, Y. Yang, Q. Chen, D. Su, X. Chen, W. Yang, J. Qiu, W. Ling, Association between serum fibroblast growth factor 21 and mortality among patients with coronary artery disease. J. Clin. Endocrinol. Metab. 101(12), 4886–4894 (2016). https://doi.org/10.1210/jc.2016-2308
M. Lenart-Lipinska, B. Matyjaszek-Matuszek, W. Gernand, A. Nowakowski, J. Solski, Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up. Diabetes Res. Clin. Pract. 101(2), 194–200 (2013). https://doi.org/10.1016/j.diabres.2013.04.010
Acknowledgements
We thank Eva Schriver, Annette Mengel, Lisa Buus, and Kirsten Nyborg Rasmussen at The Medical Research Laboratory, Aarhus University for technical assistance.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of The Central Denmark Region Committees on Health Research Ethics (1-10-72-255-15) and of the Danish Data Protection Agency (1-16-02-83-16) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Rosell Rask, S., Krarup Hansen, T. & Bjerre, M. FGF21 and glycemic control in patients with T1D. Endocrine 65, 550–557 (2019). https://doi.org/10.1007/s12020-019-02027-3
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DOI: https://doi.org/10.1007/s12020-019-02027-3