The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
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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In the citing paper
“Furthermore, patients with obesity-related insulin resistance have an impaired FGF21 upregulation after exercise [156,157].”
In the citing paper
“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].”
In the citing paper
“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]”
In the citing paper
“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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Cites
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
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
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
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
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
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
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
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
The role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500
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
Cited by
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Muscle–Organ Crosstalk: The Emerging Roles of Myokines
Severinsen, M. C. K., & Pedersen, B. K. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa016 · Cited by 1,226
“The Fibroblast growth factor 21 (FGF-21) (150) and Follistatin (151) are released from human liver during exercise and this release is controlled by the glucagon-to-insulin ratio (152).”
BackgroundSelf-citationKalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882
Physical activity and muscle-brain crosstalk
Pedersen, B. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0174-x · Cited by 772
Self-citationThe Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › 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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