Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes
Abstract
CONTEXT: Hepatokines have emerged as liver-derived hormone-like factors. Plasma fibroblast growth factor (FGF)-21 and follistatin increase with a high glucagon to insulin ratio and exercise, and resting levels are elevated in patients with type 2 diabetes (T2D). OBJECTIVE: The objective of the study was to investigate the regulatory roles of glucagon to insulin ratio and T2D on exercise-induced FGF21 and follistatin secretion. Design /Interventions: Young healthy males performed a 2-hour bicycle exercise bout followed by 5 hours of rest in supine position with and without a pancreatic clamp blocking the increase in the glucagon to insulin ratio. In addition, we evaluated exercise-induced plasma FGF21 and follistatin in patients with T2D compared with healthy controls in response to 1 hour of bicycle exercise followed by a 3-hour recovery period. RESULTS: In healthy individuals, we observed a 10-fold (P < .002) increase in the glucagon to insulin ratio during exercise, which was abolished by the pancreatic clamp. Exercise with the pancreatic clamp completely blunted the exercise-induced increase in FGF21 (P = .007), whereas the induction of follistatin was approximately 50% reduced (P = .04). Exercise-induced FGF21 secretion was completely absent in patients with T2D, whereas the exercise-induced follistatin increase was impaired. CONCLUSIONS/INTERPRETATION: Exercise-induced increases in plasma FGF21 and follistatin are attenuated by the pancreatic clamp, indicating important roles for glucagon and insulin as upstream regulators. For follistatin, an additional regulatory mechanism must exist. Our data further show that exercise-induced FGF21 and follistatin secretion are impaired in patients with T2D. The magnitude of changes in glucagon and insulin or the sensitivity to these hormones seems central in the regulation of FGF21 and follistatin in humans.
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Patients with obesity-related insulin resistance have an impaired FGF21 upregulation after exercise.
“Furthermore, patients with obesity-related insulin resistance have an impaired FGF21 upregulation after exercise [156,157].”
Patients with obesity-related insulin resistance present increased basal levels of follistatin, but its exercise-induced release by the liver is blunted.
“Expectedly, like FGF21, patients with obesity-related insulin resistance present increased basal levels of follistatin [157,180], but its exercise-induced release by the liver is blunted [157].”
Clinical studies in patients with insulin resistant conditions have described dampened upregulation of exercise-induced factors such as FGF21 and follistatin, most likely due to an altered glucagon-to-insulin ratio.
“Clinical studies in patients with insulin resistant conditions have described dampened upregulation of exercise-induced factors, such as FGF21 and follistatin, most likely due to an altered glucagon-to-insulin ratio [156,157,280]”
Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters.
“Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters in these patients [188,191,192] (Table 1).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [192]
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2 retracted
Berglund, E. D., Kang, L., Lee, R. S., Hasenour, C. M., Lustig, D. G., Lynes, S. E., Donahue, E. P., Swift, L. L., Charron, M. J., & Wasserman, D. H. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00263.2010 · Cited by 100 · see citing works
RetractedHepatic Glucagon Action Is Essential for Exercise-Induced Reversal of Mouse Fatty Liver
Berglund, E. D., Lustig, D. G., Baheza, R. A., Hasenour, C. M., Lee, R. S., Donahue, E. P., Lynes, S. E., Swift, L. L., Charron, M. J., Damon, B. M., et al. (2011) · Diabetes · doi:10.2337/db11-0455 · Cited by 44 · see citing works
RetractedInagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504 · see citing works
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151 · see citing works
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885 · see citing works
Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease
Dushay, J., Chui, P. C., Gopalakrishnan, G. S., Varela–Rey, M., Crawley, M., Fisher, F. M., Badman, M. K., Martinez–Chantar, M. L., & Maratos–Flier, E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.04.054 · Cited by 607 · see citing works
Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
Markan, K. R., Naber, M. C., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M., & Potthoff, M. J. (2014) · Diabetes · doi:10.2337/db14-0595 · Cited by 590 · see citing works
Gälman, C., Lundåsen, T., Kharitonenkov, A., Bina, H. A., Eriksson, M., Hafström, I., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.014 · Cited by 512 · see citing works
The role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500 · see citing works
Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis
Amthor, H., Nicholas, G., McKinnell, I., Kemp, C. F., Sharma, M., Kambadur, R., & Patel, K. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.01.046 · Cited by 401 · see citing works
Chavez, A. O., Molina-Carrion, M., Abdul-Ghani, M. A., Folli, F., DeFronzo, R. A., & Tripathy, D. (2009) · Diabetes Care · doi:10.2337/dc09-0684 · Cited by 390 · see citing works
Acute Exercise Induces FGF21 Expression in Mice and in Healthy Humans
Kim, K. H., Kim, S. H., Min, Y.-K., Yang, H.-M., Lee, J.-B., & Lee, M.-S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063517 · Cited by 290 · see citing works
Gilson, H., Schakman, O., Kalista, S., Lause, P., Tsuchida, K., & Thissen, J.-P. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00193.2009 · Cited by 248 · see citing works
Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
Habegger, K. M., Stemmer, K., Cheng, C., Müller, T. D., Heppner, K. M., Ottaway, N., Holland, J., Hembree, J. L., Smiley, D., Gelfanov, V., et al. (2013) · Diabetes · doi:10.2337/db12-1116 · Cited by 245 · see citing works
Hansen, J., Brandt, C., Nielsen, A. R., Hojman, P., Whitham, M., Febbraio, M. A., Pedersen, B. K., & Plomgaard, P. (2011) · Endocrinology · doi:10.1210/en.2010-0868 · Cited by 200 · see citing works
Self-citationKim, H., Méndez, R., Zheng, Z., Chang, L., Cai, J., Zhang, R., & Zhang, K. (2014) · Endocrinology · doi:10.1210/en.2013-1490 · Cited by 134 · see citing works
Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio
Hansen, J. S., Rutti, S., Arous, C., Clemmesen, J. O., Secher, N. H., Drescher, A., Gonelle-Gispert, C., Halban, P. A., Pedersen, B. K., Weigert, C., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3668 · Cited by 125 · see citing works
Self-citationGlucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans
Hansen, J. S., Clemmesen, J. O., Secher, N. H., Hoene, M., Drescher, A., Weigert, C., Pedersen, B. K., & Plomgaard, P. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.06.001 · Cited by 123 · see citing works
Self-citationHepatokines: unlocking the multi-organ network in metabolic diseases
Iroz, A., Couty, J.-P., & Postic, C. (2015) · Diabetologia · doi:10.1007/s00125-015-3634-4 · Cited by 111 · see citing works
Hansen, J. S., Zhao, X., Irmler, M., Liu, X., Hoene, M., Scheler, M., Li, Y., Beckers, J., de Angelis, M. H., Häring, H., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3584-x · Cited by 90 · see citing works
Self-citationA complex role of activin A in non-alcoholic fatty liver disease
Yndestad, A., Haukeland, J. W., Dahl, T. B., Bjøro, K., Gladhaug, I. P., Berge, C., Damås, J. K., Haaland, T., Løberg, E. M., Linnestad, P., et al. (2009) · The American Journal of Gastroenterology · doi:10.1038/ajg.2009.318 · Cited by 75 · see citing works
Hansen, J., Rinnov, A., Krogh‐Madsen, R., Fischer, C. P., Andreasen, A. S., Berg, R. M. G., Møller, K., Pedersen, B. K., & Plomgaard, P. (2013) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2415 · Cited by 71 · see citing works
Self-citationJaspan, J. B., Polonsky, K. S., Lewis, M., Pensler, J., Pugh, W., Moossa, A. R., & Rubenstein, A. H. (1981) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1981.240.3.e233 · Cited by 68 · see citing works
Follistatin: A Novel Therapeutic for the Improvement of Muscle Regeneration
Yaden, B. C., Croy, J. E., Wang, Y., Wilson, J. M., Datta‐Mannan, A., Shetler, P. K., Milner, A., Bryant, H. U., Andrews, J., Dai, G., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211169 · Cited by 64 · see citing works
Vamvini, M. T., Aronis, K. N., Chamberland, J. P., & Mantzoros, C. S. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1665 · Cited by 53 · see citing works
Attenuated fibroblast growth factor 21 response to acute aerobic exercise in obese individuals
Slusher, A. L., Whitehurst, M., Zoeller, R. F., Mock, J. T., Maharaj, M., & Huang, C.-J. (2015) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2015.06.002 · Cited by 50 · see citing works
Changes in Serum Levels of Myokines and Wnt-Antagonists after an Ultramarathon Race
Kerschan‐Schindl, K., Thalmann, M., Weiss, E., Tsironi, M., Föger‐Samwald, U., Meinhart, J., Skenderi, K., & Pietschmann, P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132478 · Cited by 46 · see citing works
Increased hepatic glucose production response to glucagon in trained subjects
Drouin, R., Lavoie, C., Bourque, J., Ducros, F., Poisson, D., & Chiasson, J. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.1.e23 · Cited by 38 · see citing works
Miyanaga, K., & Shimasaki, S. (1993) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(93)90080-4 · Cited by 37 · see citing works
Overcoming Insulin Insufficiency by Forced Follistatin Expression in β -cells of db/db Mice
Zhao, C., Qiao, C., Tang, R., Jiang, J., Li, J., Martin, C. B., Bulaklak, K., Li, J., Wang, D. W., & Xiao, X. (2015) · Molecular Therapy · doi:10.1038/mt.2015.29 · Cited by 37 · see citing works
Regulation of the expression of follistatin in rat hepatocytes
Zhang, Y.-Q., Kanzaki, M., Shibata, H., & Kojima, I. (1997) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(97)00085-7 · Cited by 36 · see citing works
Relationship between arterial and portal vein immunoreactive glucagon during exercise
Wasserman, D. H., Lacy, D. B., & Bracy, D. P. (1993) · Journal of Applied Physiology · doi:10.1152/jappl.1993.75.2.724 · Cited by 33 · see citing works
Nielsen, M. F., Wise, S., Dinneen, S. F., Schwenk, W. F., Basil, A., & Rizza, R. A. (1997) · Diabetes · doi:10.2337/diab.46.12.2007 · Cited by 30 · see citing works
Increased density of glucagon receptors in liver from endurance-trained rats
Légaré, A., Drouin, R., Milot, M., Massicotte, D., Péronnet, F., Massicotte, G., & Lavoie, C. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.1.e193 · Cited by 26 · see citing works
Altered action of glucagon on human liver in Type 2 (non-insulin-dependent) diabetes mellitus
Arner, P., Einarsson, K., Ewerth, S., & Livingston, J. N. (1987) · Diabetologia · doi:10.1007/bf00299025 · Cited by 8 · see citing works
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Severinsen, M. C. K., & Pedersen, B. K. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa016 · Cited by 1,226 · see citing works
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Kruse, R., Vienberg, S. G., Vind, B. F., Andersen, B., & Højlund, K. (2017) · Diabetologia · doi:10.1007/s00125-017-4373-5 · Cited by 69 · see citing works
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Boa, B. C. S., Yudkin, J. S., van Hinsbergh, V. W. M., Bouskela, E., & Eringa, E. C. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13732 · Cited by 64 · see citing works
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Self-citationIngerslev, B., Hansen, J. S., Hoffmann, C., Clemmesen, J. O., Secher, N. H., Scheler, M., Hrabĕ de Angelis, M., Häring, H. U., Pedersen, B. K., Weigert, C., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.06.018 · Cited by 61 · see citing works
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Self-citationSargeant, J. A., Aithal, G. P., Takamura, T., Misu, H., Takayama, H., Douglas, J. A., Turner, M. C., Stensel, D. J., Nimmo, M. A., Webb, D. R., et al. (2018) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2017-0639 · Cited by 56 · see citing works
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Dantas, W. S., Roschel, H., Murai, I. H., Gil, S., Davuluri, G., Axelrod, C. L., Ghosh, S., Newman, S. S., Zhang, H., Shinjo, S. K., et al. (2020) · Diabetes · doi:10.2337/db19-1180 · Cited by 54 · see citing works
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Loyd, C., Magrisso, I. J., Haas, M., Balusu, S., Krishna, R., Itoh, N., Sandoval, D. A., Pérez–Tilve, D., Obici, S., & Habegger, K. M. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00456.2016 · Cited by 46 · see citing works
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Townsend, L. K., MacPherson, R. E. K., & Wright, D. C. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab333 · Cited by 35 · see citing works
Khalafi, M., Alamdari, K. A., Symonds, M. E., Nobari, H., & Carlos-Vivas, J. (2021) · HORMONES · doi:10.1007/s42000-020-00245-3 · Cited by 34 · see citing works
Circulating Follistatin and Activin A and Their Regulation by Insulin in Obesity and Type 2 Diabetes
Sylow, L., Vind, B. F., Kruse, R., Møller, P. M., Wojtaszewski, J. F. P., Richter, E. A., & Højlund, K. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa090 · Cited by 34 · see citing works
Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone
Phillips, K. J. (2019) · Biology · doi:10.3390/biology8030057 · Cited by 34 · see citing works
Du, Y., Xu, C., Shi, H., Jiang, X., Tang, W., Wu, X., Chen, M., Li, H., Zhang, X., & Cheng, Q. (2021) · BMC Geriatrics · doi:10.1186/s12877-021-02481-7 · Cited by 32 · see citing works
Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21
Porter, J. W., Rowles, J. L., Fletcher, J. A., Zidon, T. M., Winn, N. C., McCabe, L., Park, Y.-M., Perfield, J. W., Thyfault, J. P., Rector, R. S., et al. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0190 · Cited by 31 · see citing works
Altered GDF15 and FGF21 Levels in Response to Strenuous Exercise: A Study in Marathon Runners
Campderrós, L., Sánchez‐Infantes, D., Villarroya, J., Nescolarde, L., Bayés‐Genís, A., Cereijo, R., Roca, E., & Villarroya, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.550102 · Cited by 30 · see citing works
Yang, B., Lu, L., Zhou, D., Fan, W., Barbier‐Torres, L., Steggerda, J. A., Yang, H., & Yang, X. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1007944 · Cited by 29 · see citing works
Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice
Luo, H.-Y., Mu, W.-J., Chen, M., Zhu, J., Li, Y., Li, S., Yan, L.-J., Li, R.-Y., Yin, M.-T., Li, X., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155916 · Cited by 28 · see citing works
Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg
Langlois, A., Dumond, A., Vion, J., Pinget, M., & Bouzakri, K. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.836344 · Cited by 27 · see citing works
Moderate-Intensity Continuous Training Improves FGF21 and KLB Expression in Obese Mice
Xiong, Y., Chen, Y., Liu, Y., & Zhang, B. (2020) · Biochemistry (Moscow) · doi:10.1134/s000629792008009x · Cited by 26 · see citing works
Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus
Guo, C. Y., Zhao, L., Li, Y., Deng, X., & Yuan, G. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29879 · Cited by 21 · see citing works
Physical Activity, Obesity and Weight Loss Maintenance
Brandt, C., & Pedersen, B. K. (2022) · Handbook of experimental pharmacology · doi:10.1007/164_2021_575 · Cited by 18 · see citing works
Self-citationSabaratnam, R., Kristensen, J. M., Pedersen, A. J. T., Kruse, R., Handberg, A., Wojtaszewski, J. F. P., & Højlund, K. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae032 · Cited by 18 · see citing works
Endocrine Mechanisms Connecting Exercise to Brown Adipose Tissue Metabolism: a Human Perspective
Méndez-Gutiérrez, A., Osuna‐Prieto, F. J., Aguilera, C. M., Ruiz, J. R., & Sánchez‐Delgado, G. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01319-7 · Cited by 18 · see citing works
Vasyukova, O. V., Kasyanova, Y. V., Okorokov, P. L., & Bezlepkina, O. B. (2021) · Problems of Endocrinology · doi:10.14341/probl12779 · Cited by 18 · see citing works
Diabetes Mellitus Should Be Considered While Analysing Sarcopenia-Related Biomarkers
Rentflejsz, J., & Wojszel, Z. B. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13041107 · Cited by 17 · see citing works
Lombardi, G., Sansoni, V., & Banfi, G. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.07.11 · Cited by 15 · see citing works
Tao, R., Stöhr, O., Wang, C., Qiu, W., Copps, K. D., & White, M. F. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101703 · Cited by 14 · see citing works
Periodized low protein-high carbohydrate diet confers potent, but transient, metabolic improvements
Li, Z., Rasmussen, M. L., Li, J., Henríquez‐Olguín, C., Knudsen, J. R., Madsen, A. B., Sanchez-Quant, E., Kleinert, M., & Jensen, T. E. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.08.008 · Cited by 14 · see citing works
Lim, J. Y., & Kim, E. (2023) · Metabolites · doi:10.3390/metabo13090979 · Cited by 13 · see citing works
Exercise and inactivity as modifiers of β cell function and type 2 diabetes risk
Hall, L. G., Thyfault, J. P., & Johnson, J. D. (2023) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00472.2022 · Cited by 14 · see citing works
Do diabetes and obesity affect the metabolic response to exercise?
Plomgaard, P., & Weigert, C. (2017) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000379 · Cited by 10 · see citing works
Self-citationThe Effect of Exercise on Spexin and Follistatin in Elderly Individuals
Ayaz, E. Y., Dinçer, B., Cinbaz, G., Karacan, E., Benli, R. K., Mete, E., Bilgiç, H., & Mesçi, B. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13692 · Cited by 9 · see citing works
Tsuchiya, Y., & Goto, K. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155553 · Cited by 9 · see citing works
Liu, X., Zhang, N., Sung, B., & Wang, B. (2022) · Physiological Research · doi:10.33549/physiolres.934833 · Cited by 8 · see citing works
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Richter, M. M., & Plomgaard, P. (2021) · Journal of the Endocrine Society · doi:10.1210/jendso/bvab121 · Cited by 7 · see citing works
Self-citationKabadi, U. M. (2021) · Open Journal of Endocrine and Metabolic Diseases · doi:10.4236/ojemd.2021.113007 · Cited by 7 · see citing works
In Vivo Detection of Human Brown Adipose Tissue During Cold and Exercise by PET/CT
Nascimento, E. B. M., & Lichtenbelt, W. D. V. M. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_121 · Cited by 7 · see citing works
Roles of FGF21 and irisin in obesity-related diabetes and pancreatic diseases
Xie, T., & Leung, P. S. (2020) · Journal of Pancreatology · doi:10.1097/jp9.0000000000000039 · Cited by 7 · see citing works
Skeletal Muscle as Endocrine Organ
Ma, M., Zhang, Z., Hai, B., & Zhang, Y. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_22 · Cited by 6 · see citing works
Russell‐Guzmán, J., Karachon, L., Gacitúa, T. A., Freundlich, A., Poblete-Aro, C., & Rodrigo, R. (2018) · Sport Sciences for Health · doi:10.1007/s11332-018-0459-9 · Cited by 6 · see citing works
Vizvari, E., Farzanegi, P., & Sourati, H. A. (2020) · Medical Laboratory Journal · doi:10.52547/mlj.14.6.17 · Cited by 4 · see citing works
Zahedani, S. S., & sayadzai, N. (2018) · Medical Laboratory Journal · doi:10.29252/mlj.12.2.7 · Cited by 4 · see citing works
Pervin, S., Wilson, N. Y. A. H., Reddy, S. T., & Singh, R. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.88294 · Cited by 3 · see citing works
Roohbakhsh, E., Barari, A., & Abbaszadeh, H. (2021) · Quarterly of Horizon of Medical Sciences · doi:10.32598/hms.27.2.3456.1 · Cited by 3 · see citing works
Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
Razi, O., Zamani, N., de Moraes, C., Laher, I., & Hadjicharalambous, M. (2025) · Applied Sciences · doi:10.3390/app15116191 · Cited by 4 · see citing works
Huang, S., Chen, Z., Li, H.-M., Zheng, L., Zhou, Z., Peng, X., & Tang, C. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1642389 · Cited by 2 · see citing works
Liver–pancreas communication in disease and drug development
Jia, Y., Zhu, Q., Pan, Q., Lu, G., & Xiao, J. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.01.018 · Cited by 2 · see citing works
azhir, S., Alijani, E., Martínez-Huenchullán, S., Amni, H., Baker, J., & Farhani, F. (2022) · Retos · doi:10.47197/retos.v44i0.91770 · Cited by 2 · see citing works
Ghiyami, S. H., Afroundeh, R., Pourvaghar, M. J., Sadeghi, A., & Katebi, L. (2023) · Complementary Medicine Journal · doi:10.61186/cmja.12.4.1 · Cited by 2 · see citing works
Salisbury, D. L., Li, D., Todd, M. W., Ng, T. K. S., & Yu, F. (2023) · Journal of Vascular Diseases · doi:10.3390/jvd2030027 · Cited by 2 · see citing works
Fibroblast growth factor 21: new insights from human studies
Hansen, J. S., & Plomgaard, P. (2016) · Cardiovascular Endocrinology · doi:10.1097/xce.0000000000000084 · Cited by 2 · see citing works
Self-citationDurrer, C. G., Islam, H., Cen, H. H., Moya-Garzón, M. D., Lyu, X., McKelvey, S., Singer, J., Batterham, A. M., Long, J. Z., Johnson, J. D., et al. (2024) · Nutrition & Metabolism · doi:10.1186/s12986-024-00807-x · Cited by 2 · see citing works
Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans
Kolnes, K. J., Møller, P. M., Kruse, R., Christensen, M. H., Kjøbsted, R., Hey-Mogensen, M., Andersen, B., Handberg, A., & Højlund, K. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1797525 · Cited by 2 · see citing works
Folistatina, resistencia a la insulina y composición corporal en adultos colombianos
Toloza, F. J. K., Ricardo-Silgado, M. L., Mantilla-Rivas, J. O., Morales-Álvarez, M. C., Pérez-Matos, M. C., Pinzón-Cortés, J. A., Pérez-Mayorga, M., & Mendivil, C. O. (2018) · Revista Colombiana de Endocrinología Diabetes & Metabolismo · doi:10.53853/encr.5.1.336 · Cited by 1 · see citing works
Švecová, M., Bakalář, B., Vyklicka, K., Tomandlová, M., Böhm, J., Brenerová, P., Janošek, J., Lipový, B., Zajíček, R., & Linhartová, P. B. (2025) · Burns · doi:10.1016/j.burns.2025.107633 · Cited by 1 · see citing works
Botelho, W. G. N., César, A. R. D. A., & Teixeira, K. N. (2021) · Research Society and Development · doi:10.33448/rsd-v10i16.24223
Bock, P. M., Monteiro, R. B., Berlanda, G., Casali, K. R., & Schaan, B. D. (2022) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000482 · Cited by 1 · see citing works
Le, N. B. A., NGUYEN, H. N., & NGUYEN, T. M. N. (2023) · Tạp chí Dinh dưỡng và Thực phẩm · doi:10.56283/1859-0381/420
(2023) · Wiley eBooks · doi:10.1002/9781394236329.refs
Cross-talk between hepatokines as Liver indused-exercise factors and organokinesPreprint
Rad, R. S. (2023) · Research Square · doi:10.21203/rs.3.rs-3734627/v1
Role of Myokines and prospects for their role in Diabetes Mellitus Therapy
Nuriya, K., Farida, M., Sharma, R., Liliya, S., Mkhitaryan, X. E., Chergizova, B., Salikhova, Y., Niyazova, Y., Ryspayeva, G., Evnevich, A., et al. (2024) · Research Journal of Pharmacy and Technology · doi:10.52711/0974-360x.2024.00786
Can we run away from the metabolic side effects of antipsychotics?
Akcan, M., & Wright, D. C. (2025) · Translational Exercise Biomedicine · doi:10.1515/teb-2025-0016
- Authors
- Hansen, J. S., Pedersen, B. K., Xu, G., Lehmann, R., Weigert, C., & Plomgaard, P.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Plomgaard, Peter
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-07
- Volume
- 101
- Issue
- 7
- Pages
- 2816-2825
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2375156733
- Cited by
- 106
- References
- 35
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 13 · 2022: 9 · 2021: 17 · 2020: 15 · 2019: 9 · 2018: 12 · 2017: 8 · 2016: 4
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Dalian Institute of Chemical Physics, CAS Institutional Repository (submittedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Keywords
- FGF21, follistatin, hepatic hormones, physical activity, type 2 diabetes, glucagon, insulin, hormonal regulation
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Fibroblast Growth Factors, Glucagon, Humans, Insulin, Insulin Resistance, Male, Pancreas, Glucose Clamp Technique, Exercise, Cross-Over Studies, Follistatin, Young Adult
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